Schematic representation of a parasagittal section of the human brain, showing the neuroanatomical projections involved in parasympathetic nervous system activation for neuroprotection. (A) Afferent vagus nerve pathway (represented by deep blue color ): Afferent vagus nerve neurons synapse bilaterally on the nucleus tractus solitarius (NTS) in the medulla oblongata. The NTS makes projections to various brain structures including the locus coeruleus (LC), which is the main source of norepinephrine for the entire brain. The LC provides noradrenergic innervation to various parts of the brain, including the thalamus (Thal), hippocampus (Hp), cerebral cortex (CTX), and the forebrain cholinergic system, of which the nucleus basalis of Meynert (NBM) is a principal component. The LC also innervates the dorsal raphe nucleus (DRN). The DRN provides extensive serotonergic innervation to many brain structures including the thalamus, cerebral cortex, and hippocampus. (B) Central cholinergic and efferent vagal pathway (represented by dark blue color ): The central cholinergic system consists mainly of projections from the nucleus basalis of Meynert, the medial septal nuclei (Msn), and the pedunculopontine tegmental nucleus (PPTg). These provide cholinergic innervation to brain structures including the caudate nucleus (Cd), globus pallidus (Gp), thalamus, hippocampus, and cerebral cortex and brainstem structures. The central cholinergic system drives the efferent vagal output. (C) Parasympathetic cerebrovascular innervation (represented by pink color ): The sphenopalatine ganglion (SPG), which is a parasympathetic ganglion found in the pterygopalatine fossa, receives preganglionic neurons (Prg) from the superior salivatory nucleus (SSN). Postganglionic neurons (Psg) from the SPG enter the cranial cavity, through the ethmoidal foramina, where they provide nitroxidergic-cholinergic innervation to the major cerebral blood vessels; anterior cerebral artery (ACA), middle cerebral artery (MCA), posterior cerebral artery (PCA), and basilar artery (BA), and the communicating arteries of the circle of Willis. Cc, corpus callosum.

The neuroprotective mechanisms of parasympathetic nervous system activation. (A) Afferent vagal pathway (represented by deep blue color ): Afferent vagus nerve signals project to the dorsal vagal complex, where majority of the fibers synapse on the nucleus tractus solitarious (NTS). Through the NTS projections to the locus coeruleus (LC), vagus nerve stimulation (VNS) causes the release of norepinephrine (NE). Norepinephrine subsequently stimulates the release of serotonin (5-hydroxytryptamine, 5-HT) from the dorsal raphe nucleus (DRN). Norepinephrine stimulates neurogenesis as well as excitation of cholinergic neurons leading to acetylcholine (ACh) release and inhibition of inflammation. 5-HT stimulates neurogenesis and suppresses excitotoxicity by inhibiting glutamate release and downregulating NR2B. (B) Central cholinergic and efferent vagal pathway (represented by dark blue color ): The central cholinergic system releases ACh, which inhibits inflammation in the brain by activating α7 nicotinic acetylcholine receptor (nAChRα7), leading to suppression of cytokine release. The central cholinergic system also drives the cholinergic antiinflammatory pathway systemically via the efferent vagus nerve. (C) Parasympathetic cerebrovascular innervation (represented by pink color ): The sphenopalatine ganglion (SPG) receives preganglionic neurons from the superior salivatory nucleus (SSN). Postganglionic neurons from the SPG provide nitroxidergic innervation to the cerebral vaculature: anterior cerebral artery (ACA), middle cerebral artery (MCA), posterior cerebral artery (PCA), and basilar artery (BA). Through the release of nitric oxide (NO) stimulation of the SPG causes vasodilation and increased perfusion leading to neuroprotection. AR_α1, α₁-adrenergic receptor; NMDAR, N-methyl--aspartate receptor; ‘+' denotes stimulation, ‘−' denotes inhibition.