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Bermúdez-Rattoni F, editor. Neural Plasticity and Memory: From Genes to Brain Imaging. Boca Raton (FL): CRC Press/Taylor & Francis; 2007.

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Chapter 12Memory Impairments Associated with Stress and Aging

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Memory processes can be profoundly affected by life experiences. In particular, stress has proved to be a major modulator of memory function.1–4 However, we should bear in mind that stress is an extremely wide concept that ranges from situations that require moderate adaptations from the individual to circumstances that can be overwhelmingly adverse and persistent.

As can be expected, the impacts of such diverse stressful experiences on cognitive functions are not the same. Whereas moderate stress experienced during learning can facilitate information storage,5–7 experiencing excessive stress acutely or severe stress chronically can be highly detrimental to memory function. Moreover, substantial evidence indicates that there are important time-windows during the lifespan when experiencing stress can exert an impact on later life including detrimental consequences for cognitive performance during aging. How the two latter stress conditions (chronic stress experienced in adulthood and the developmental effects of stress on the aging process) affect memory function will be the focus of the first part of this chapter.

The second part will deal with memory alterations that characterize the aging period. In both parts, phenomenological descriptions of cognitive alterations will be followed by sections dealing with major mechanisms that have been implicated in mediating the described effects of stress or aging.

12.1. STRESS

12.1.1. Concept of Stress

Before dealing with the different topics related to stress, aging, and memory interactions, important issues in relation to the concept of stress and stress physiology must be introduced. Stress is considered to imply any challenge to the homeostasis of an individual that requires an adaptive response of that individual.8

Since life is a cumulative exposure to changing and challenging situations, virtually all living organisms experience stress, more or less frequently, during their life spans.

Although stress is a loose concept that historically has meant different things for different authors, today we recognize the importance of distinguishing three components that together define every stress experience.

12.1.1.1. Stressors

Stressors are stimuli, generally aversive and potentially harmful, that exert impacts on individuals. Stressors can be classified as either exteroceptive (extreme temperatures, electric shocks, social situations) or interoceptive (ranging from health problems such as gastric disturbances to psychogenic problems such as unjustified fear).

12.1.1.2. Evaluation of Situation

The way an individual interprets a potentially stressful situation is a critical step to determine whether a specific stimulus acts as a stressor. A sudden noise can be judged as dangerous by one individual and experienced as harmless by another. Their respective reactions can depend on many factors such as previous experiences with similar noises, or may be based on the expectations that each individual generates about the potential consequences derived from that particular noise. Various psychological processes are important, with controllability or the ability to cope with the situation serving as a very important factor in determining how stressful situations are experienced.9–11

12.1.1.3. Response of Individual

Response includes both physiological and behavioral reactions to a stressful situation. The physiological stress reaction typically comprises central (sensory, emotional, and cognitive processing of stimuli by the central nervous system) and peripheral (activation of the sympathetic nervous system and the hypothalamus–pituitary–adrenal axis) responses (see below). The behavioral reactions include both direct responses to the specific stressors and adaptive responses that are addressed to optimize survival.8

12.1.2. Physiological Stress Response

The stress response involves a complex reaction in the organism that, in addition to the activation of peripheral stress systems, includes the activation of specific circuits in the brain. Most of these neural circuits have the capacity not only of processing information, but also eventually affect the degree and direction of activation of peripheral physiological systems.12 As to the peripheral responses, the two major systems activated during stress are the sympathetic (SNS) branch of the autonomic nervous system (ANS) and the neuroendocrine system consisting of the hypothalamus–pituitary–adrenocortical (HPA) axis.

12.1.2.1. Sympathetic Nervous System

Unlike the parasympathetic branch of the ANS that mediates calm vegetative functions such as growth, digestion, and relaxing responses of the organism, the SNS is stimulated by activating and stressful situations. This system comprises a number of projections that connect with virtually every organ in the body where they secrete norepinephrine.

An important projection of the SNS is its input to the medulla of the adrenal glands, where adrenaline and noradrenaline hormones are secreted into the bloodstream. Many well-known responses to stress are caused by activation of the SNS, including increased heart rate and blood pressure, increased glucose levels, increased muscle tension, and increased sweating. In parallel, activation of the SNS delays functions that are not directly required to survive at that particular moment; typical examples are the lessening or suspension of digestion and reproduction.

12.1.2.2. Hypothalamus–Pituitary–Adrenal Axis

Most of the work examining the deleterious effects of stress on memory function has focused on the HPA axis (Figure 12.1). This neuroendocrine system involves the sequential activation of messenger molecules produced by the hypothalamus, the pituitary, and the adrenal cortex. The main hypothalamic HPA messengers, corticotrophin releasing hormone (CRH) and vasopressin (AVP), are synthesized in the paraventricular nucleus. Upon the appropriate stimulus, these peptides are released and, through the portal vein system, get access to the anterior pituitary where they stimulate the production and release of the adrenocorticotropic hormone (ACTH) into the bloodstream. Eventually, ACTH reaches the adrenal cortex where it stimulates the secretion and production of glucocorticoids (cortisol in humans; corticosterone in a variety of animals including rodents).

FIGURE 12.1. The hypothalamus–pituitary–adrenal axis.

FIGURE 12.1

The hypothalamus–pituitary–adrenal axis. Activation of the hypothalamus results in a chain of events that eventually result in the release of glucocorticoids. Once in the bloodstream, these steroid hormones exert negative feedback at the (more...)

Glucocorticoids are steroid hormones that produce extensive effects on virtually all physiological systems. Among their many roles, they exert essential feedback actions at a variety of levels (prefrontal cortex, hippocampus, hypothalamus, and pituitary) to inhibit the activity of the axis. Such negative feedback is crucial to suppress excessive levels of these steroids, whose brief action can be highly adaptive, but their maintenance at high levels for prolonged periods can be highly detrimental to an organism.

Due to their lipophilic nature, glucocorticoids can achieve rapid access to the brain. In addition to rapid nongenomic actions through membrane receptors, glucocorticoids affect the brain by acting through two classical intracellular corticosteroid receptors that exert genomic effects.13 They are the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). Corticosterone binds with a 10-fold higher affinity to MRs than to GRs and therefore it is not surprising that many stress effects are mediated through GRs. The hippocampus shows the highest density of corticosteroid receptors, with some amygdala nuclei and the prefrontal cortex also showing moderate to high levels of GRs.1

12.1.3. Stress and Memory Function

As noted above, stress covers a wide spectrum of circumstances that can eventually have differential effects in the acquisition, consolidation, and retrieval of information. Based on the importance for mental health of the negative effects that highly stressful circumstances can impinge on cognitive function, the focus of this chapter is on the detrimental effects of stress on memory processes.3,4,6,14 For reviews on the positive aspects of moderate brief stress periods on memory formation, see References 5, 7, and 15. A number of important factors related to stress and cognition must be taken into account when trying to understand how stress affects cognitive function. The following parameters are particularly important.

12.1.3.1. Stress Magnitude and Intensity

Intuitively, the impacts of extreme stressors (such as a real life threat, for example, a strong earthquake) on cognitive function are expected to differ greatly from those impinged by moderate stressors (such as exposure to novelty), and experimental evidence largely supports this view.16,17 In any case, it is important to note the drastic individual differences in stress reactivity existing among conspecifics. Therefore, when evaluating the impact of stress intensity, it is advisable to take into account both the specific characteristics of the stressor and measure individual behavioral and physiological responses in order to determine the actual stress magnitude experienced by each experimental subject.

12.1.3.2. Stressor Timing

The time when stress is experienced with regard to the cognitive function under evaluation seems to be a crucial factor of both the types of effects observed and the mechanisms implicated.17 Depending on whether stress is experienced before, during, or after the cognitive challenge, different processes (acquisition, consolidation, and/or retrieval of information) can be affected. Consistent evidence indicates that acute stress exerts different effects on consolidation (frequently facilitating) and retrieval (frequently impairing) of information.5–7,17

12.1.3.3. Stressor Duration

As we will see in the following sections, taking into account the duration of the stressor is essential, particularly when the question under analysis is related to the mechanisms whereby stress impairs cognitive function. We will review the experimental work that illustrates impaired memory function following either acute or chronic stress (see below).

12.1.3.4. Stressor Controllability

Substantial work in humans and animals indicates that an individual’s perception of his or her ability to cope with a stressful experience has profound consequences on the degree of cognitive alteration induced by stress. Uncontrollable stressors generally provoke more behavioral impairments than controllable stressors, and many neurochemical changes ordinarily elicited by uncontrollable stressors are not observed when control is possible.10,11,18 However, recent evidence suggests that the different impacts produced by controllable and uncontrollable stressors in the brain may not be due simply to the contribution of uncontrollability, but may in fact be affected by the ability to control. By using a triadic design (see Figure 12.2), the medial prefrontal cortex (mPFC) was proposed to inhibit stress-induced neural activity in brainstem nuclei (notably, the dorsal raphe nucleus) in individuals who exerted control over stress in contrast to the prior view that such brainstem activity was induced by the lack of control.19

FIGURE 12.2. Cartoon representing classic triadic design used to evaluate behavioral and physiological impacts of exposure to controllable or uncontrollable stress in rats.

FIGURE 12.2

Cartoon representing classic triadic design used to evaluate behavioral and physiological impacts of exposure to controllable or uncontrollable stress in rats. The design involves three groups. Two were submitted to stress (electric shocks in the tail) (more...)

In addition to the memory phase under study (see Section 12.1.3.2, “Stressor Timing”), other factors are also important to take into account with regard to the cognitive function under study.

12.1.3.5. Factors Related to Memory Processes

As mentioned above, not all phases in the information process related to memory function are equally susceptible to disruption by stress. It is, therefore, very important to design experiments that allow one to establish which memory phase (acquisition, consolidation, retrieval, or even reconsolidation) is affected by the stress procedure under study (Figure 12.3).

FIGURE 12.3. Depiction of the importance of the timing when stress is experienced with regard to the phase of information processing under study.

FIGURE 12.3

Depiction of the importance of the timing when stress is experienced with regard to the phase of information processing under study. If stress is given before acquisition of information (1), it can potentially affect all cognitive phases involved in memory (more...)

Another particularly important factor is the type of learning process evaluated (i.e., implicit/procedural explicit/declarative, nonassociative learning, etc). Notably, implicit memory processes have been shown to be positively influenced by stress.20,21 Both acute20–22 and chronic23–25 stress experiences were reported to potentiate associative types of learning such as eyeblink conditioning and fear conditioning in male (but not female20) rodents. On the contrary, explicit/declarative/relational types of memories are much more vulnerable to interference by stress. Since this chapter covers the detrimental effects of stress on memory, we will mainly focus on these latter types of memory that have been shown to be particularly vulnerable to alteration by stress.

12.1.4. Acute Stress and Memory Impairment

Experiencing an acute highly stressful situation can interfere with subsequent information processing. This holds true particularly for those circumstances in which a stressed individual is required to retrieve previously stored information while the acquisition of new information is shown to be particularly resistant to disruption in experimental animals. In fact, most rodent studies in which acute stress has been applied before animals were confronted to learn a hippocampus-dependent task failed to find alterations in the acquisition rate.26,27 If any consistent effects were observed, in most cases they were not evident in the performance of animals during the training (or learning) phase, but appeared in subsequent retention tests.

For example, Baker and Kim28 showed that exposure to uncontrollable stress can affect a nonspatial task, the object-recognition memory. In their study, rats given inescapable restraint and tail-shock stress just before exposure to a novel object recognition task showed normal memory when tested 5 min after first exposure to objects, but were impaired when tested 3 hours later. Control rats displayed a preference for a novel object (over a familiar one) when they were tested at different time delays (5 min and 3 hours). Unlike the unstressed controls, at the 3-hour posttraining test, stressed animals spent comparable time exploring novel and familiar objects.

When the impact of stress on the retrieval of previously acquired information was directly assessed, similar detrimental results on retention were reported. De Quervain et al.29 found that exposing rats to either stress or glucocorticoids 30 min before testing impaired retention performance in the spatial task Morris water maze. Convincing evidence indicates that the level of difficulty of the task (memory load) is a critical factor in observing the detrimental effects of stress on retrieval processes. Using the radial arm water maze (RAWM; a modified Morris water maze that contains four or six arms, with a hidden platform located at the end of one of them), Diamond et al.30 showed that exposure to a cat during a 30-min delay period between training and testing for the platform location (the platform was located in the same arm on each trial within a day and was in a different arm across days) had no effect on memory in the easiest RAWM, but stress impaired memory in more difficult versions of the RAWM. By lesioning the hippocampus, the authors also confirmed that the RAWM is a hippocampal-dependent task.

In addition to the importance of memory load (difficulty or memory demand of the task), it seems that flexible forms of memory are particularly susceptible to show disrupted retrieval by stress, as opposed to more stable ones that remain largely unaffected.31 In humans, stress or pharmacological glucocorticoid treatments given just before retrieval have also been found to impair the recovery of information.7,32–35 As in animals, memory load is also an important factor for stress-induced retrieval impairments in humans.33 Interestingly, the effect of stress in memory retrieval seems to be related to the emotional content of the information. For example, psychosocial laboratory stress (as induced by the Trier Social Stress Test) was shown to particularly impair recall of emotionally arousing but not of neutral words.36 Therefore, emotionally arousing material appears to be especially sensitive to the impairing effects of stress in retrieval.

12.1.5. Neurobiological Mechanisms Involved in Acute Effects of Stress on Memory

Cognitive and neurobiological studies have provided converging evidence that the hippocampus is critically involved in long-term memory formation37–39 and also a primary central nervous system target of stress hormones.2,6 The great sensitivity of the hippocampus to stress is revealed by the profound suppression of hippocampal synaptic plasticity after acute exposure to stressors40–44 or increased glucocorticoids.44 Moreover, adrenergic activation in the basolateral amygdala and hippocampus was shown to be critical for the impairing effects of glucocorticoids on delayed memory retrieval in spatial water maze tasks.45

A crucial role for the medial temporal lobe (and the hippocampus in particular) in mediating these stress-induced retrieval impairments is also supported by human neuroimaging studies.33 Specifically, de Quervain et al.33 used positron emission tomography (PET) to investigate the effects of pharmacologically increased glucocorticoid levels in regional cerebral blood flow during declarative memory retrieval in healthy male humans. A single stress-level dose of cortisone (25 mg) given 1 hour before testing impaired cued recall of word pairs learned 24 hours earlier but did not significantly affect performance in other tasks such as verbal recognition, semantic generation, and categorization. Simultaneously, this treatment resulted in a large decrease in regional cerebral blood flow in a number of brain areas including the right posterior medial temporal lobe, left visual cortex, and cerebellum. The decrease in the right posterior medial temporal lobe was maximal in the parahippocampal gyrus, a region associated with successful verbal memory retrieval.

In addition to the hippocampus, evidence indicates that acute stress-induced memory impairing effects can also be mediated by activation of dopaminergic46,47 and noradrenergic48 transmission in other structures known to be involved in high-order (including working memory and executive function) processing such as the prefrontal cortex (PFC).

Only a few studies have been reported on potential molecular mechanisms whereby stress could lead to less effective functioning of neural networks during retrieval. Recently, the potential role of the neural cell adhesion molecule (NCAM) was investigated in a rat model of stress-induced retrieval deficits in the RAWM by cat stress.49 NCAM (see Figure 12.4) is a part of a family of cell surface glycoproteins that play key roles in neural development and in synaptic plasticity in the adult brain.50–52 Encoded by a single gene, the three main isoforms derived by alternative splicing are NCAM-120, NCAM-140, and NCAM-180 according to their approximate molecular weights. In addition to playing roles in cell–cell recognition and synapse stabilization, NCAM also participates in neurite outgrowth, activation of signal transduction cascades, and synapse formation and elimination.53,54 Moreover, NCAM has been implicated in the induction of hippocampal long-term potentiation (LTP; a physiological model of memory) and in memory formation.50–52 Finally, these molecules have been shown to be sensitive to stress.4

FIGURE 12.4. Cell adhesion molecules of the immunoglobulin superfamily NCAM and L1.

FIGURE 12.4

Cell adhesion molecules of the immunoglobulin superfamily NCAM and L1. Left: the molecular structures of these molecules are represented. NCAM has three major isoforms that differ in molecular weight and type of attachment to cell membranes. Right: two (more...)

In the cat stress study,49 rats were trained to locate a hidden platform and then during a 30-min delay period they were either left undisturbed or exposed to a cat, after which all animals were given retention trials and brain samples [hippocampus, basolateral amygdala (BLA), PFC, and cerebellum] were extracted immediately afterward to assess for NCAM levels in synaptosomal preparations. Two other control groups were included: a group of undisturbed rats submitted only to handling and a swim control group that was exposed to the maze but not to spatial learning. The platform location changed from trial to trial.

NCAM expression in the hippocampus was not altered in animals with intact spatial memories that were not stressed. However, predator exposure impaired spatial memory and dramatically reduced NCAM levels in the hippocampus (particularly the NCAM-180 isoform) and PFC (although specificity of the PFC effect is questioned since reduced NCAM levels were also found in trained but unstressed animals and in the swim control group). No significant changes in NCAM levels were observed in the amygdala or cerebellum. These observations of drastic reductions of NCAM in stressed memory-impaired rats is consistent with an increasing body of data indicating that hippocampal NCAM is important for long-term memory formation.55–58 The drastic suppression of hippocampal NCAM levels found in the hippocampus after rat stress may also contribute to impaired long-term consolidation and/or retrieval processes of spatial memory.

12.1.6. Impairing Effects of Chronic Stress on Cognitive Function

Prolonged exposure to stress is now recognized as a condition that can induce deleterious effects on brain structure and cognition2,59,60 and increase the risks of developing neuropsychiatric disorders.61,62 Since most of the pioneer work in the field focused on the hippocampus as a primary target of stress actions,2,63,64 the possibility that chronic stress affects hippocampal-dependent learning has been extensively tested. Chronically stressed male rats were shown to exhibit learning and memory deficits in a variety of spatial tasks including the radial-arm maze,65 the Y maze,66 the radial-arm water maze,67 and the Morris water maze.57,68

Evidence from the animal and human literature supports the existence of considerable variability in the vulnerability to stress among conspecific individuals.69–72 Numerous studies have reported important individual differences in the impact exerted by stress in learning, memory, and retrieval processes.70–73 While some individuals are particularly vulnerable, others may be resistant to the effects of stress. These differences may be due to predisposing factors, to previous life experiences or, more likely, to both. Given the devastating consequences that stress impinges in susceptible individuals, developing tools able to predict which individuals are in particular danger would be of great value for developing more effective strategies to prevent and/or reverse the effects of adverse life periods. Three types of factors have been identified as particularly important in influencing an individual’s susceptibility to develop cognitive alterations under chronic stress: (1) certain personality traits; (2) gender; and (3) age.

12.1.6.1. Personality Traits

The level of locomotor activity displayed by rats in a novel environment has been identified as an accurate index to categorize individuals with relevant psychobiological profiles.74,75 By exposing rats to novelty, it is possible to classify them in groups, one comprising those that exhibit a high locomotor activity (high-responding or HR) and another including those that present low levels of activity (low-responding or LR). See Figure 12.5. This behavioral trait of novelty reactivity in rats has been proposed to resemble some of the features of high-sensation seekers in humans.76

FIGURE 12.5. One of the classic experimental procedures used to characterize animals on the behavioral trait of novelty reactivity.

FIGURE 12.5

One of the classic experimental procedures used to characterize animals on the behavioral trait of novelty reactivity. Animals were exposed to a novel environment (open field is depicted in the figure; circular corridors are classically used) and their (more...)

Individual differences in reactivity to novelty in adult male rats have been related to differences in susceptibility to develop cognitive alterations after exposure to chronic stress.77 Specifically, when 4-month old LR and HR Wistar male rats were submitted to psychosocial stress for 21 days (daily cohabitation of each young adult rat with a new middle-aged rat), HR, but not LR, rats subsequently showed marked deficits in spatial learning in the water maze.

Anxiety trait is a well-known risk factor for the development of stress-related neuropsychiatric disorders, like depression in humans,78,79 and it has been associated with degrees of cognitive impairment following chronic stress in rodents. Specifically, peripubertal anxiety levels of male rats (as evaluated using open field and elevated plus mazes at 43 days of age) were shown to be predictive of the detrimental effects of chronic restraint stress (21 days) on hippocampal-dependent spatial memory as assessed in young adulthood (75 days). Memory was tested on the spatial Y-maze using two inter-trial interval levels of difficulty (1 min or 4 hours). No differences among groups were observed in the less difficult 1-min version of the Y-maze. However, in the 4-hour version of the Y-maze, chronically stressed high anxiety rats — but not the other groups — showed impaired spatial memory. Moreover, a month after the chronic stress ended, high anxiety rats had significantly higher basal corticosterone levels than low anxiety rats (control and stress). In fact, anxiety trait in rats was also found to predict impaired spatial learning performance in the stressful water maze task under acute conditions80 that highlight anxious individuals as particularly prone to show cognitive deficits under stressful conditions.

12.1.6.2. Gender

The importance of gender on the effects of stress in cognition remained elusive until recently due to the routine use of only male rodents in behavioral studies. However, intensive work over the past few years involving female rodents shows that gender is indeed a critical factor in an individual’s susceptibility to chronic stress.81,82

When both male and female rats were submitted to chronic stress procedures (such as 21 days of chronic restraint stress), males were impaired in all tasks in which they were tested (novel object recognition and two spatial memory tasks: object placement and radial arm maze), while females were either enhanced (spatial memory tasks) or not impaired (nonspatial memory tasks).83 As indicated below, age seems to be an important factor in the modulatory role of gender in stress and memory interactions.

12.1.6.3. Age

Age has been identified as a critical factor in the interactions between stress and cognition from two main perspectives. One is related to a differential susceptibility to stress that is manifested by some individuals at different times across the life span. The second relates to the impact that experiencing stress at a particular life period might have in future cognitive functioning.

With regard to the first perspective, aging has been clearly identified in male rats as a risk factor for developing stress-induced cognitive impairments. A pioneer study by Bodnoff et al.84 in young adult and mid-aged male rats showed that mid-aged rats were more vulnerable to the effects of chronic corticosterone administration. Three months of steroid treatment at doses sufficient to mimic the elevated hormone levels observed following exposure to mild stress induced learning impairments in the mid-aged but not young, rats in the Morris water maze. Mid-aged rats exposed for 6 months to high social stress were also pronouncedly impaired in spatial learning. This effect was prevented by adrenalectomy. This and related findings85,86 (see below) highlight midlife as a time of particular sensitivity to the effects of chronic stress and corticosteroid hormones.

Interestingly, the effects of aging seem to be gender-dependent. A recent review of the literature82 pointed out that whereas the impairing effects of stress on male rodents are observed across the whole lifespan, females show more variable responses to stress. Stress-induced facilitations observed in females in young adulthood were not further observed following stress exposure at old age.82

The second perspective implies that exposure to stress at a particular life period may have long-term and/or delayed consequences in memory function. Early life experiences are known to exert profound influences in stress reactivity in adulthood and cognitive aging.62,87 Much work has been done with early postnatal stress manipulations88–91 which, in addition to affecting other behavioral and physiological aspects in later adulthood, consistently resulted in learning and memory deficits in hippocampus-dependent tasks such as the water maze.

Interestingly, a recent study has presented evidence that some consequences of early-life stressful experiences may not be manifested during young adulthood, then become apparent later during midlife. Brunson et al.92 explored whether psychological early-life stress in rats caused an enduring deterioration of hippocampal function that worsened from young adulthood to middle age. To induce stress, environment and maternal behavior were altered by placing pups and dams in cages with limited nesting and bedding material on postnatal days 2 to 9. This resulted in abnormal nurturing behavior in the dams including reduced and fragmented nursing and grooming of pups. The selection of such procedure was based on its ability to produce substantial neuroendocrine changes early in life93 that become fully normalized by adulthood.92 Although the offspring showed virtually normal cognitive function during young adulthood (4 to 5 months of age), they were severely impaired in hippocampus-dependent tasks (spatial learning in the water maze and novel object recognition) at mid-age (12 months). The authors suggested that stress during periods of hippocampal development may permanently influence hippocampal systems that are particularly vulnerable during these periods.89,94

Substantial work indicates that lifetime exposure to stress can also affect cognitive function at aging. This is discussed in detail below, after the next section that provides a general overview on the main neurobiological mechanisms that have been implicated in the deleterious actions of chronic stress on memory function.

12.1.7. Neurobiological Mechanisms Involved in Deleterious Effects of Chronic Stress on Brain and Behavior

First, it is important to note that the mechanisms whereby chronic stress impairs cognitive function are not necessarily the same as the ones mediating acute stress effects. While neural alterations involved in acute stress effects seem to be mainly mediated by dynamic functional alterations among cellular and molecular interactions, chronic stress is now known to have a major impact on both functional aspects and neuronal structures. In this section, the main structural and functional effects of chronic stress on specific neural circuits will be discussed, followed by an overview of the molecular processes reported to contribute to such effects.

12.1.7.1. Structural Effects of Chronic Stress

Because many examples in the literature indicating impairing effects of chronic stress in memory processes were obtained in hippocampus-dependent tasks, the hippocampus is the brain region that has received the most attention. However, intensive work during the past few years is providing increasing evidence for a more integral impact of chronic stress throughout the brain that, as illustrated below, is now documented to a certain extent at the level of the prefrontal cortex and amygdala.

Hippocampus

The hippocampus plays a central role in memory processes,39,95 particularly in spatial learning which is generally affected by stress manipulations.96 In humans, neuroimaging studies have reported hippocampal atrophy in association with stress- and glucocorticoid-related cognitive and neuropsychiatric alterations.97–99 In rodents, the CA3 subregion appears to be particularly vulnerable to the effects of chronic stress. In rats subjected to stress for 3 to 4 weeks, CA3 has been reported to experience the following structural alterations:

  • Dendritic atrophy of apical CA3 pyramidal neurons100,101 (Figure 12.6)
  • A striking reorganization within mossy fiber terminals102
  • Synaptic loss of excitatory glutamatergic synapses57,103
  • A reduction in the surface area of postsynaptic densities103
  • A marked retraction of thorny excrescences104
FIGURE 12.6. Structural effects of chronic stress in the hippocampus and amygdala.

FIGURE 12.6

Structural effects of chronic stress in the hippocampus and amygdala. Different hippocampal subregions can be markedly affected by exposure to chronic stress. The upper part of the figure represents the stress-induced atrophy of apical dendrites in CA3 (more...)

Although stress-induced alterations in CA1 morphology are not as drastic as those occurring in CA3, some changes have also been reported in this hippocampal subregion (particularly in excitatory axospinous synaptic connectivity in rat CA1 stratum lacunosum moleculare) after stressing rats for 3 to 4 weeks. These changes include:

  • Alterations in the lengths of the terminal dendritic segments of pyramidal cells in rat CA1103
  • Increases in postsynaptic density surface area and volume in CA1 stratum lacunosum moleculare105
  • An overall reduction of the dorsal anterior CA1 area volume105

In addition, stress and high glucocorticoid levels can suppress neurogenesis in the dentate gyrus106 (Figure 12.6). Furthermore, stress can compromise cell survival and eventually lead to overt neuronal loss by exacerbating the neurotoxicity induced by other hippocampal insults.107

Prefrontal cortex

The prefrontal cortex (PFC), particularly its medial part (mPFC), is critically involved in higher cognitive processes and in the integration of cognitive and emotionally relevant information.108–110 Moreover, the PFC contains high levels of glucocorticoid receptors111,112 and is also involved in the regulation of stress-induced hypothalamic–pituitary–adrenal (HPA) activity.113 Clinical evidence highlights mPFC as a core alteration in a wide variety of neuropsychiatric disorders.114,115

Rodent studies have provided evidence that major neuronal remodeling occurs in the mPFC as a consequence of repeated exposure to chronic stress or repeated glucocorticoid treatment. Chronic stress also results in major changes in layer II/III of the PFC following 21 days of repeated stress:

  • Dendritic atrophy: decrease of total length116,117 and number116 of apical dendrites from pyramidal neurons.
  • Spine loss: a decrease in apical dendritic spine density. It is estimated that nearly one-third of all axospinous synapses on apical dendrites of pyramidal neurons in medial PFC are lost following repeated stress.118

Glucocorticoids seem to be major players in the remodeling induced by stress in the mPFC. Rats chronically treated (4 weeks) with either corticosterone (25 mg/kg) or dexamethasone, a synthetic glucocorticoid (300 μg/kg), showed neuronal loss and atrophy of layer II of the infralimbic, prelimbic, and cingulate cortices.119 Moreover, morphological studies have established that chronic daily corticosterone injections (3 weeks) in rats resulted in dendritic reorganization in pyramidal neurons in layer II-III of the mPFC,120 with major changes observed in apical arbors consisting of increased dendritic material proximal to the soma and decreased dendritic material distal to the soma.

Amygdala

The amygdala plays key role in emotional behavior and especially in fear.121 It is not yet clear whether this structure is involved in the deleterious effects of stress in memory function since amygdala-dependent memories such as fear conditioning are potentiated by chronic stress.23,24

Strikingly, the structural alterations that have been observed in the amygdala contrast with the dendritic atrophy observed in the hippocampus or PFC. Repeated exposure of rats to restraint stress (10 days) induced enhanced dendritic branching of pyramidal and stellate neurons in the BLA122 (Figure 12.6). This effect was dependent on the stressor used, since no changes were observed in these neuronal types following a chronic unpredictable stress procedure that, instead, induced atrophy only in BLA bipolar neurons.122 Moreover, the restraint procedure also resulted in increased spine density across primary and secondary branches of spiny neurons in the BLA.123

Further studies are needed to confirm whether sensitization of amygdala activation occurring as a consequence of sustained stress exposure may also be an important component of the reported memory impairments in more explicit types of memories.

12.1.7.2. Effects of Chronic Stress on Synaptic Plasticity

Electrophysiological experiments have consistently shown impaired synaptic plasticity following chronic stress, indicative of functional consequences on neural circuits of the structural alterations described above. Thus, long-term potentiation (LTP) is impaired in different hippocampal areas including CA1,124,125 the commissural/associational (but not mossy fiber) input to CA3,126 and the dentate gyrus.124 Likewise, treating rats chronically with corticosterone was found to impair hippocampal synaptic potentiation.84,127 Moreover, evidence indicates stress-inducing changes in LTP in the mPFC–amygdala pathway.128

Interestingly, early-life stress can also result in late-onset hippocampal dysfunction. Early-life stress in rats causes a decline in a number of measures of synaptic function and plasticity (LTP in CA1 and CA3 hippocampal subregions) when evaluated at mid-age (12 months).92

12.1.7.3. Molecular Alterations Induced by Chronic Stress

A number of molecular mechanisms seem to participate in the deleterious effects induced by stress in brain structure and cognitive function. Certain neurotransmitters, signal transduction pathways, neurotrophic factors, and adhesion molecules have been implicated in the effects of chronic stress on the brain.4,5,59,107,129

Excitatory amino acids

Alterations in glutamatergic transmission have been proposed to result in an excitotoxic cascade of mechanisms finally leading to neuronal endangerment and/or neurotoxicity.107 In line with evidence that stress and glucocorticoids increase glutamate levels in the hippocampus and other brain regions,130–132 glutamate has been involved in the deleterious effects of stress and corticosterone on hippocampal structure.100,101 Furthermore, increased NMDA and decreased AMPA receptor density have been reported in the hippocampus after exposure to stress.133–135 In parallel, NMDA-mediated synaptic responses were found to be increased after chronic stress.136

Neurotrophic factors

Changes in neurotrophin levels have been hypothesized to play a key role in stress-induced neuronal damage. Hippocampal BDNF is reduced both by stress and glucocorticoid137 treatments. Conversely, fibroblast growth factor-2 (FGF-2) expression was shown to be increased after both stress and glucocorticoid treatments, which might represent a neuroprotective mechanism to preserve neuronal viability in challenging situations.129

Moreover, stress can influence intracellular transduction pathways involved in neurotrophin receptor signaling as shown for Ras-MAP kinase cascades138,139 that play critical roles in synaptic plasticity and neuronal survival. Chronically stressed rats also showed severe and lasting hyperphosphorylation of the extracellular signal-regulated kinases ERK1 and ERK2 involved in the Ras–MAP kinase pathway, along with a decrease in phospho-CREB expression in a number of areas including the hippocampus.138,140 Interestingly, phosphorylated CREB modulates the transcription of several genes that code for molecules involved in neuronal plasticity including tyrosine hydroxylase, BDNF, and NCAM.

Cell adhesion molecules

Chronic stress can markedly affect the expression of cell adhesion molecules in the hippocampus. Exposure of rats to chronic stress for 21 days has been reported to result in:

  • Reduced mRNA and protein expression NCAM in the hippocampus.24,68 Although the expression of the mRNA coding for the NCAM-180 isoform was not altered,68 chronic stress specifically reduced NCAM-140 protein expression.77,141 Moreover, a milder but widespread decrease in NCAM mRNA levels was observed across other brain areas.68
  • Post-translational modification of NCAM with -2,8-linked polysialic acid (PSA) is also profoundly affected by chronic stress that increases its hippocampal expression24 in the dentate gyrus.142 In addition to its role in cell–cell de-adhesion, PSA-NCAM has been associated with newly generated cells143 since this post-translational modification of PSA-NCAM contributes to the migration of new progenitors and neurons. However, because chronic stress actually decreases cell proliferation in the dentate gyrus, the PSA-NCAM increase induced by stress cannot be attributed to a secondary effect on neurogenesis.141 Interestingly, the effects of stress on NCAM polysialylation are not restricted to the hippocampus. Chronic stress was also reported to enhance PSA-NCAM expression in the piriform cortex144 and reduce it in several amygdala nuclei.145
  • Increased L1 mRNA and protein expression in the hippocampus24,68. Like NCAM, L1 is another cell adhesion molecule of the immunoglobulin superfamily that has been largely implicated in synaptic plasticity and memory formation.50 Based on the neuroprotective effects of this molecule, a neuroprotective role has been hypothesized for the stress-induced increases of L1.4

Early postnatal stress was also reported to cause a profound reduction of NCAM expression in the hippocampus and cortex when the rats reached adulthood.91

12.1.8. Stress and Aging

Aging is a period during which individual differences in cognitive abilities become larger, both in humans146–149 and rodents.150–152 Lifetime exposure to stress and the corresponding increases in glucocorticoid hormones have been proposed to be critical factors contributing to variability in the aging process.60,153–156 In particular, exposure to stress or high levels of glucocorticoids has been implicated in the acceleration and/or exacerbation of cognitive deficits in elderly subjects.14,59,60,154,157–159 Therefore, in addition to enhancing the magnitude of cognitive disturbances observed in aged individuals, stress may also accelerate their appearance.

Aging is associated with higher basal cortisol levels160 and reduced feedback sensitivity of the HPA axis to pharmacological challenges.161,162 A role for stress and stress hormones in cognitive deficits at aging is also supported by the finding that rats classified as inferior (as opposed to good) learners when aged over 22 months showed both impaired memory and increased corticosterone levels.157,163,164 Moreover, hippocampal corticosteroid receptors have been also implicated in aging-associated increased glucocorticoid levels and the accompanying alterations on negative feedback regulation of the HPA axis.1,165

In most rat strains, aging has been linked to decreased MR binding and/or expression, with alterations in GR function being normally mild or nonexistent.166–169 In addition to the hippocampus, differences in GR expression were found in aged rats (24 months), depending on their capability to learn the water maze task.170 Specifically, old rats classified as superior learners had lower expression of GR mRNA in the parvocellular paraventricular nucleus of the hypothalamus than aged inferior learners. In parallel, aged inferior learners showed exaggerated stress-induced ACTH responses.170

As stated above, middle age seems to be a relevant time for stress and neuroendocrine interactions with the subsequent aging processes. Middle-aged rats (10 to 12 months old) were shown to be more vulnerable than younger rats to stress- or glucocorticoid-induced cognitive disturbances.84,85 Also, interfering with age-associated increases in corticosterone levels by submitting rats to adrenalectomies at 12 months was found to prevent age-related cognitive impairment (in reversal learning) as well as certain alterations in hippocampal structure.158

The importance of individual differences in the impact of stress experienced at mid-age on accelerating cognitive decline is illustrated in a recent study.86 Male rats were classified according to their locomotor reactivities to novelty as either highly reactive (HR) or low reactive (LR) as young adults and submitted to chronic stress (1 month) during mid-age (12 months). At early aging (18 months), their learning abilities were tested in the water maze and a number of neuroendocrine (plasma corticosterone, hippocampal corticosteroid receptors) and neurobiological (hippocampal expression of neuronal cell adhesion molecules) parameters were evaluated. Impaired learning was observed in stressed HR rats. Increased hippocampal mineralocorticoid receptors were found in stressed LR rats when compared with stressed HR and control LR groups. Moreover, mid-life stress induced an increased corticosterone response and a reduction in NCAM-180 isoform and L1 regardless of the behavioral trait of novelty reactivity. These findings support the view that stress experienced throughout life can contribute to cognitive impairment occurring during the early aging period.

Likewise, evidence in aged humans also supports such a link among increasing glucocorticoid levels, memory deficits, and hippocampal atrophy.159 In particular, aged humans with significant prolonged cortisol elevations were found to display reduced hippocampal volumes and deficits in hippocampus-dependent memory tasks as compared to normal-cortisol controls.159 More recently, Wolf et al.171 reported that individuals who complain about memory impairments (in the absence of measurable impairments) have enhanced HPA axis activity as indicated by both higher basal cortisol levels and higher cortisol levels after dexamethasone.

12.2. AGING

Age-associated cognitive impairment has been described in a variety of species, including rats, macaque monkeys and humans.172–175 In this second part of the chapter, I will review the main memory alterations that characterize cognitive decline associated with aging in humans and experimental animals (notably rodents). In each case, the neurobiological mechanisms linked to such declines will follow the phenomenological descriptions.

12.2.1. Memory Deficits in Aging Human Population

As stated above, there are considerable individual differences in the course of aging, with particularly large variation occurring in humans.148 Establishing what represents normal cognitive decay is complicated by the difficulties of distinguishing stable mild impairments and deficits related to early symptoms of neurodegenerative diseases such as Alzheimer’s disease that show progressive deteriorations of brain function and behavior.174 In fact, most aged humans experience some form of age-related neural pathology such as Alzheimer’s disease (AD), Parkinson’s disease, diabetes, hypertension, and arteriosclerosis. Other difficulties for determining the cognitive alterations due to aging are the limitations intrinsic to the types of studies that can be done with human subjects. Instead of providing proper experimental evidence, studies on aged human subjects normally provide only correlational evidence and therefore cannot be considered highly conclusive. Moreover, these studies are frequently based on cross-sectional evaluations of individuals of different age groups. The limitation relates to comparing groups that may differ in the sociological impacts of living their respective life periods during different decades. However, the recent trend is to perform longitudinal studies, most of the current ones focusing on longitudinal changes occurring after the age of 60.

However, normal aging is also associated with changes in the neural basis of cognition. Regardless of individual differences, aging influences certain memory types and cognitive fields more than others. In general terms, as indicated by both cross-sectional and longitudinal studies, aging is characterized by considerable reductions in certain capacities:176–179

  • Speed of information processing
  • Working memory
  • Formation of new episodic memories
  • Spatial learning

Other abilities such as emotional processing, short-term memory, autobiographical memory, semantic knowledge, and priming remain relatively intact.174–180 Cumulative knowledge suggests that the identified memory deficits are mainly the consequences of age-related changes in two types of cognitive processes:

  • Disrupted executive functions that eventually exert major consequences on a variety of memory functions. The importance of executive function for memory is mainly related to the controlled processing frequently required during the encoding (particularly when strategic elaboration is required) and retrieval (when an active searching strategy is required) of information. For example, one cognitive process that is particularly dependent on executive processes that are disrupted in aging is the recall of the source of information and temporal details of past episodes.
  • Decay of long-term declarative memory.174

Recent findings suggest that the personal appraisal of the changes that come with aging is an important factor that determines who is not greatly impaired by aging and who deteriorates rapidly. Wellbeing and a positive view of aging seem to act as major protective factors against the detrimental effects of age, not only on brain and cognitive function, but also at a more general level of the organism.181 It seems that, at odds with older adults showing rapid declines, those who are not much impaired in their cognitive abilities may show compensation for brain decline in aging that involves increased recruitment of brain activity during cognitive performance.

12.2.2. Neurobiological Mechanisms Associated with Age-Related Cognitive Decline in Humans

There is great interest in understanding the neurobiological mechanisms that underlie memory decline occurring at aging and identifying the factors that determine differential impacts of aging on various cognitive domains and on different individuals. In agreement with the behavioral alterations observed in executive function and declarative memory, neuroimaging studies have shown that age-related cognitive deficits are linked to multiple structural and functional changes in the frontal–striatal circuits, medial temporal lobe (MTL), regions and white matter tracts.174

Thus, the deficits of executive function observed in the nondemented aged population have been associated with alterations in frontal–striatal circuits. A variety of pathophysiological changes that have been reported to occur in frontal–striatal areas in the aged population may account for the reported executive difficulties.173

At the structural level, multiple changes including atrophy of frontal grey matter and striatal volume loss have been reported. Neurotransmitter systems can also experience considerable alteration during the aging process. An age-associated decline in dopamine content, for example, appears to be associated with executive impairments.

Frontal white matter appears to be particularly susceptible to age-related damage (showing diffuse changes and small infarcts), and a link with the degree of cognitive impairment has been established in studies linking behavioral testing with structural magnetic resonance imaging (MRI) evaluating white matter lesions. This latter pathology seems to be related to problems in vascular function (mainly hypertension) that appear to have a special impact on white matter structures supporting frontal–striatal circuits.

On the other hand, the characteristic alterations of long-term declarative memory occurring during aging have been linked to age-related changes in the MTL, including the hippocampus and adjacent regions. The MTL is strongly affected in AD (from its earlier stages), with a number of pathophysiological features characterizing the damage to these structures. These include atrophy, cell loss, and cellular damage, and are consistently associated with marked memory deficits. More specifically, cellular pathology in AD is linked to abnormal extracellular deposition of amyloid protein and intracellular accumulations of tau.182

Substantial evidence supports a key role of deposits (plaques) and soluble forms of amyloid on the triggering of neuronal dysfunction and eventual cell death. Such deposits also lead to neurofibrillary tangles that represent a major pathology in the MTL and eventually spread to associated cortex. In AD, the symptoms progress to the eventual overall impairment as the disease advances. Recent imaging studies suggest that what may account for the memory impairment observed in this disease is the disruption of a network of connections including the MTL and other areas, notably the precuneus, extending into retrosplenial and posterior cingulate cortex.173 In any case, it is important to note that the circuits that degenerate in AD are also vulnerable to normal aging, but the vulnerability is reflected by compromised synaptic communication rather than by neuron death.183

One interesting feature indicated by functional imaging studies of non-demented old individuals is that unique patterns of brain activation distinguish older individuals showing high-performance in cognitive tasks from younger adults.184 A subset of older adults showed increased recruitment of brain areas that has been interpreted as a potential compensatory response to increasing task difficulty.173 They may require the use of additional brain resources to guarantee a certain performance level when other physiological alterations interfere with their cognitive functions. This type of compensatory process has been proposed to play a role in individual differences in cognitive decline during the course of aging.

12.2.3. Memory Deficits in Aged Rodents

Research on experimental animals is essential for gaining insight into what is normal cognitive decline associated with aging and what is pathological. It is also necessary to our understanding of the relative involvement of different factor with age differences in cognition. Most commonly, rodents are used to characterize age-related alterations in memory processes and ascertain the neurobiological processes underlying such cognitive deficits.

Although aged rodents display a variety of cognitive deficits, a large part of the research on this topic has focused on the hippocampus and spatial learning. Before reviewing that issue, we will deal with methodological aspects that are relevant to research in this area, then present a brief discussion of the research carried out in rodents to explore the degree of alteration on frontal lobe functions in these animal species.

12.2.3.1. Methodological Aspects of Aging Research in Rodents

Given the relatively short life-spans of rodents (normally 2 to 4 years), they are particularly appropriate for longitudinal studies that are ideal for obtaining aging curves and collecting information about essential factors contributing to developmental decline. However, they are also the exceptions rather than the rules in animal research because they are both expensive and time-consuming. The most frequent approach, as in human studies, is the use of cross-sectional comparisons of groups of animals of different ages, typically including young adults and older individuals.185

The study of aging involves a number of difficulties that are particularly relevant when the focus of research is cognition.186 Aging is generally associated with changes in sensorimotor abilities and motivation, factors that can impact the performances of animals in learning and memory tasks but should be distinguished from putative impairments in cognitive performance.187 Particularly, visual competence can be highly degraded in aging rats, an aspect that should be specially controlled when studying animal performance of tasks with visual components.188

Another factor that requires special attention is that rodents that have been maintained undisturbed in their home cages during the course of their lives may not be appropriate subjects for cognitive testing at old age. Rodents raised in animal houses are normally not confronted with environmental challenges. Therefore, their organisms had no opportunities to adapt and to develop behavioral and physiological strategies relevant for successful performance of many learning and memory tasks.187 One solution proposed to overcome this problem is to raise and house rats in enriched environments.

12.2.3.2. Alterations in Frontal Lobe Function in Aged Rodents

Most animal research that has addressed the behavioral alterations associated with frontal lobe dysfunction has been performed on non-human primates. The cognitive deficits observed (deficits in delayed response testing, increased perseveration, difficulties in reversal learning, etc.) were strikingly similar to those reported in aged humans and in young nonhuman primates with frontal lesions.189 However, a more limited number of studies in old rats could also detect similar cognitive impairments that were also comparable to those induced in younger rats by specific frontal lobe lesions. Using different behavioral testing procedures (notably delayed nonmatch to sample), clear evidence was obtained that the temporal organization of memory is significantly disrupted in aged rats, in a similar way as that observed in younger rats with prefrontal cortical damage.190,191

Evidence for impaired cognitive flexibility mediated by prefrontal circuits in aged rats has been provided using an attentional set-shifting task. Barense et al.192 trained young and aged male rats on two problems. The reward was always associated with the same stimulus dimension (for example, they had to link the reward to a particular odor) and a reversal of one problem (for example, they had to make a new association because the reward was predicted by an alternative odor and not by the former odor). Then, a new problem was presented in which the reward was consistently associated with the previously irrelevant stimulus dimension (extradimensional shift or EDS). For example, odors no longer predicted the reward; the digging medium in which the reward was hidden predicted it. Aged rats were significantly impaired on the EDS, although some individual aged rats performed as well as young rats on this phase. Moreover, some aged rats were impaired on the reversal. These deficits of the EDS paralleled those manifested by young rats submitted to neurotoxic lesions of medial frontal cortex. The impairment of rapid reversal learning observed in aged rats was linked to orbitofrontal cortex dysfunction.193

12.2.3.3. Alterations in Medial Temporal Lobe–Hippocampal Function in Aged Rodents

Due to the great interest in understanding the mechanisms underlying hippocampal dysfunction at aging, a large number of studies focused in characterizing the performance of aged rodents in spatial learning tasks. For reviews see References 194 through 196. Age-related spatial learning deficits were reported, for example, in the radial-arm maze. Aged rats were slower than younger adult rats in learning to this task,197–199 an effect that is clearly dependent on the requirement to develop a spatial strategy since aged rats were shown to be impaired in nonspatial reference memory versions of the radial-arm maze.200

Consistent deficits in learning, memory, and the acquisition of new response solutions have also been found in aged rodents trained in the Barnes circular platform task,201 in which animals learn to identify which of 18 holes distributed along the perimeter of a circular platform allows them access to a tunnel to escape eventually from exposure to light.151,201 Similar age-related deficits have also been reported in the Morris water maze spatial learning task.202–205 Aged rats normally take longer to learn the location of the hidden platform, while they show no signs of impairment when trained in a cued platform version.203,206

An assessment of hippocampal-dependent spatial learning and memory capabilities of healthy aged rodents revealed striking individual differences.207–209 For example, the water maze task revealed the existence of important individual differences in spatial memory abilities within old rats.152,207,210–212 While some animals show clear deficits in spatial memory, others perform similarly to younger animals and represent a very interesting tool for investigating the neurobiological substrates of cognitive aging (see below).

12.2.4. Aging and Structural and Functional Plasticity

Based on the well reported individual differences in cognitive aging, one of the most popular strategies in current research is to first characterize aged animals in a learning task to subsequently investigate neurobiological correlates of the observed learning and memory deficits.

A pioneer study showed in aged rats (22 to 24 months) a correlation between the degree of decline in performance in learning and place navigation tasks and brain energy metabolism (evaluated as regional glucose utilization) in 5 of 45 brain regions examined: dentate gyrus, medial septum-diagonal band area, hippocampal CA1, hippocampal CA3, and prefrontal cortex. Learning impairments in the aged rats were related to the extent of decrease in glucose utilization in restricted areas of the limbic system.213

12.2.4.1. Structural and Neurochemical Alterations

The literature contains controversy as to whether normal aging is accompanied by a loss of neurons214,215 because the most recent findings seem not to confirm earlier reports indicating such cell death. However, consensus is greater on the view that alterations in relevant neurocircuits may underlie age-related cognitive deficits.183

Human and monkey studies reported regressive changes with age in dendritic arbors and spines of cortical pyramidal neurons in specific regions and layers of the frontal lobe.216–218 Evidence of degeneration in the PFC was found both in old monkeys and humans, as indicated by drastic alterations in the morphology of terminal dendrites and reduction of synaptic and spine densities.183

Synaptic alterations are believed to be associated with changes in the expression levels of glutamate receptors, with available evidence indicating decreases in N-methyl-D-aspartic acid (NMDA; particularly the NR2B subunit) and -amino-5-hydroxy-3-methyl-4-isoxazole propionic acid (AMPA) receptors in older individuals.219,220 In addition, degeneration of myelinated axons in both deep cortical layers and white matter has been reported to correlate with sensory and cognitive capabilities in old animals.221

At the MTL, the hippocampus is the brain area more deeply studied. Using unbiased stereological methods, Geinisman et al.222 reported a decrease in the number of axospinous synapses in the mid-molecular layer of the dentate gyrus of aged rats (28 months) that was hypothesized to underlie reductions in the amplitude of excitatory postsynaptic potentials and the decline in functional synaptic plasticity detected in the dentate gyrus of senescent rats.

The cholinergic and monoaminergic systems that project from the basal forebrain and brainstem also displayed functional impairments in aging.223 Interestingly, signal transduction pathways seem to be differentially regulated in the aged hippocampus and PFC. Whereas activation of the cAMP/protein kinase A (PKA) pathway has been proposed as a mechanism for improving age-related hippocampus-related cognitive deficits, agents that increase PKA activity impair — instead of improving —prefrontal cortical function in aged rats and monkeys with prefrontal cortical deficits. Conversely, PKA inhibition was shown to ameliorate prefrontal cortical cognitive deficits.224 These findings further illustrate the complexity and difficulty in understanding the mechanisms affecting cognitive function in the aged brain.

12.2.4.2. Functional Alterations

There is controversy in the literature as to whether aged animals show deficits in hippocampal LTP.196 In general terms, age-related LTP-induction deficits are mainly found when the induction protocols involve low-intensity stimulation, but no consistent alterations are observed when high-intensity and robust stimulation is applied.196,201 Moreover, the threshold for LTP induction is increased in aged rats, which may be related to the greater difficulties displayed by aged rats to encode memories. As to LTP maintenance, whenever high-intensity stimulation has been used, age-related maintenance deficits appear at late recording time points,196,201 LTP maintenance deficits have been correlated with impaired performance in hippocampus-dependent learning tasks, including the Barnes circular platform task,151

As to long-term depression (LTD) and depotentiation, in contrast to LTP, these are more readily produced in aged than in adult rats.196 A recent study224 investigated whether LTD in area CA1 is related to individual differences in learning abilities in the outbred Long-Evans rat strain. Young rats exhibited larger NMDAR-dependent LTD (NMDAR-LTD) than the aged animals (24 months), and no differences were found between the aged unimpaired and the aged impaired groups. When an NMDAR-independent form of LTD (non-NMDAR-LTD) was examined, the aged unimpaired group showed significantly larger non-NMDAR-LTD than either the young or the aged impaired groups.

The authors also found a significant correlation between the magnitude of non-NMDAR-LTD and learning abilities in aged, but not in young, rats. This study suggests that high-performing aged rats maintain the ability to generate LTD through mechanisms different from those used by young adults, whereas aged animals that fail to make a switch to the mechanisms that mediate LTD will be impaired in learning performance.

Interestingly, variability in escape and spatial learning in the water maze in the aged unimpaired (outbred male Wistar rats 28 to 30 months old), but not in aged impaired (selected from a large pool based on water maze escape performance over a 9-day period) group was correlated with variability in short-term and long-term potentiation.152

12.2.4.3. Aged Hippocampus and Place Cells

Recent evidence indicates that the older hippocampus may also be slower to switch between cognitive maps and that such failure to switch between hippocampal maps in time may account for their impaired spatial performance.225 Spatial abilities in rodents have been largely related to hippocampal neurons called place cells that encode spatial information defined by visual landmarks226 or by self-motion cues.227 A cognitive map of an animal’s environment would be formed by a population of place cells activated by multiple cues on that particular environment.228 Rosenzweig et al.225 found that the ability of rats to find a reward in a particular environment is correlated with the ability of place cells to switch between two different cognitive maps, one based on self-motion cues that are unrelated to the task and another based on relevant landmark cues. Interestingly, old rats were impaired relative to young adult rats, both in switching from the irrelevant to the relevant map and in finding the reward.

12.3. CONCLUSIONS

Stress is a potent modulator of brain structure, brain function, and cognition. Although not all types of stress are deleterious to memory function, there are many instances in which stress (both acute and chronic) interferes with explicit types of memory, both in humans and animals (Figure 12.7). Stress hormones are also strong modulators of brain development, and excessive stress experienced at certain time windows of vulnerability during life can profoundly affect cognitive function at later stages, with a particular impact on cognitive aging. In fact, exposure to chronic stress seems to recapitulate cognitive deficits observed at aging, as well as accelerating the decline in memory function that characterizes senescence.

FIGURE 12.7. Exposure to stress outside the context of cognitive testing can have impairing effects on memory function.

FIGURE 12.7

Exposure to stress outside the context of cognitive testing can have impairing effects on memory function. Hippocampus-dependent memory processes such as spatial learning or explicit/declarative types of learning processes are particularly vulnerable (more...)

In addition to a number of neurobiological similarities (including reduced expression of NCAM or altered levels of corticosteroid receptors), both chronic stress and aging have been associated with increased basal levels of glucocorticoid hormones and impaired negative feedback causing delayed high glucocorticoid levels after their activation. In all instances, the deleterious effects of stress and aging seem to particularly impair hippocampus- and prefrontal cortex-dependent memory processes. One of the main challenges of future research will be identifying key factors that determine individual differences in vulnerability to both stress and aging.

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Bookshelf ID: NBK3914PMID: 21204432

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