Septohippocampal cholinergic system at the intersection of stress and cognition: Current trends and translational implications

Abstract

Deficits in hippocampus-dependent memory processes are common across psychiatric and neurodegenerative disorders such as depression, anxiety and Alzheimer's disease. Moreover, stress is a major environmental risk factor for these pathologies and it exerts detrimental effects on hippocampal functioning via the activation of hypothalamic-pituitary-adrenal (HPA) axis. The medial septum cholinergic neurons extensively innervate the hippocampus. Although, the cholinergic septohippocampal pathway (SHP) has long been implicated in learning and memory, its involvement in mediating the adaptive and maladaptive impact of stress on mnemonic processes remains less clear. Here, we discuss current research highlighting the contributions of cholinergic SHP in modulating memory encoding, consolidation and retrieval. Then, we present evidence supporting the view that neurobiological interactions between HPA axis stress response and cholinergic signalling impact hippocampal computations. Finally, we critically discuss potential challenges and opportunities to target cholinergic SHP as a therapeutic strategy to improve cognitive impairments in stress-related disorders. We argue that such efforts should consider recent conceptualisations on the dynamic nature of cholinergic signalling in modulating distinct subcomponents of memory and its interactions with cellular substrates that regulate the adaptive stress response.

Keywords: cholinergic; hippocampus; medial septum; memory; stress.

Figure 1.

Schematic of the septohippocampal circuit on a sagittal view of a rodent brain. Magnified views of the local circuity are depicted for septum (dashed circles) and hippocampus (solid rectangle). Solid lines represent afferents originating from the medial septum (MS) and projecting to the hippocampus. Dashed lines represent reciprocal projections (efferents) from the hippocampus directly to the MS or indirectly through the lateral septum (LS). Color and shape-code specifies neuron-type and where axonal projections terminate. Positive and negative signs represent excitatory and inhibitory connections, respectively.

Figure 2.

An illustration depicting bidirectional modulation of memory components with hippocampal cholinergic tone. Higher hippocampal acetylcholine (ACh) during awake and rapid-eye movement (REM) sleep states facilitate encoding of novel, spatial, and contextual information by favoring extrinsic pathways from neocortex to the hippocampus. Additionally, increasing ACh levels suppress retrieval of previously acquired information by inhibiting intrinsic pathway in the hippocampus to prevent interference. Reduced hippocampal tone during the slow wave sleep (SWS) facilitate consolidation of declarative memories by favoring the transfer of information from hippocampus to neocortex for long-term storage.

Figure 3.

Schematic illustration of the model depicting cholinergic regulation of hippocampal theta. Activation of both direct pathways via cholinergic neurons in the medial septum (MS), and indirect pathways through MS GABAergic neurons, to the hippocampus, are required for theta entrainment and maintenance of memory encoding and retrieval. Peaks of hippocampal theta precisely synchronizes with the spiking activity of pyramidal neurons of the CA1 subfield and entorhinal cortex, while the troughs of theta synchronizes with spiking activity of CA3 pyramidal neurons.

Figure 4:

Dynamics of cholinergic SHP and cognitive impairments in stress-related pathologies. The hypocholinergic response in the hippocampus causing cognitive decline in age-related neuropathologies is hypothesized to be primarily driven by stress-mediated atrophy of MS cholinergic neurons. On the contrary, stress-induced maladaptive hyperactivity of local hippocampal cholinergic circuits contributes to cognitive impairments associated with mood disorders.

Figure 5:

Schematic depicting potential therapeutic targets to improve episodic memory impairments in stress-related psychiatric disorders and neurodegenerative conditions. Physiological stress activates HPA-axis that results in the secretion of CRF and glucocorticoids. Cholinergic SHP is an important target of these mediators that is implicated in regulating the adaptive HPA-axis stress response. Hippocampal cholinergic transmission differentially regulates discrete subcomponents of episodic memory and optimal ACh signaling is critical for efficient memory encoding and retrieval, and cortical gating of information for consolidation. Maladaptive stress in different pathologies (such as depression, anxiety, and AD) is associated with dysregulated HPA-axis and aberrations in hippocampal cholinergic signaling that result in impaired pattern separation and disruption of episodic memories. Therefore, therapeutic strategies to optimize cholinergic signaling could potentially focus on cellular targets that are either upstream or downstream of cholinergic SHP. The upstream targets include stress signaling mediators such as CRF₁ and glucocorticoid receptors that interact with MS cholinergic neurons and hippocampal synapses. Another potential target could be CRF-BP, a CRF sequestering protein, which regulates the physiological effects of CRF. Thus, modulators of these stress mediators may hold promise to normalize dysregulated cholinergic signaling and improve memory. Downstream targets include cholinergic receptors including M1/M2/M4 mAChRs and α7/α4β2 nAChRs and strategies to develop ligands that modulate these receptors may improve pattern separation by making episodic memories of positive and negative experiences distinct during storage. Another strategy to maintain adequate levels of ACh in hippocampal networks is by exploiting stress-sensitive transcriptional component of AChE. Lastly, deep brain stimulation of MS neurons could be another approach to synchronize cholinergic mediation of hippocampal theta.