Septohippocampal Acetylcholine: Involved in but not Necessary for Learning and Memory?

Abstract

The neurotransmitter acetylcholine (ACh) has been accorded an important role in supporting learning and memory processes in the hippocampus. Cholinergic activity in the hippocampus is correlated with memory, and restoration of ACh in the hippocampus after disruption of the septohippocampal pathway is sufficient to rescue memory. However, selective ablation of cholinergic septohippocampal projections is largely without effect on hippocampal-dependent learning and memory processes. We consider the evidence underlying each of these statements, and the contradictions they pose for understanding the functional role of hippocampal ACh in memory. We suggest that although hippocampal ACh is involved in memory in the intact brain, it is not necessary for many aspects of hippocampal memory function.The goal of this review is to consider the role of septohippocampal acetylcholine (ACh) in learning and memory processes. The evidence in this regard falls broadly into two different classes. On the one hand, considerable data implicate septohippocampal ACh in memory function. This system is engaged during memory processing, indexed by ACh release or by modification of cholinergic markers, and manipulations that affect memory produce parallel changes in hippocampal cholinergic activity. Furthermore, agents that increase hippocampal cholinergic function are sufficient to reverse memory impairments caused by disruption of the septohippocampal system. However, data from studies of selective lesions of septohippocampal cholinergic neurons with the immunotoxin 192 IgG-saporin call into question the essential role of this system in learning and memory, because these studies generally failed to find severe impairments in memory function. Our goal in this article is to review the data underlying each of these lines of evidence, and to attempt to reconcile these apparently disparate observations.The discrepancy between these lines of evidence might imply that septohippocampal ACh is involved in memory processing, but is not necessary for it to occur. This viewpoint would allow for correlated changes in ACh release and memory, and for the ability of cholinergic agents to reverse memory impairments caused by disruption of septohippocampal function. However, it also would permit memory to proceed relatively normally in the absence of septohippocampal cholinergic input. By describing this viewpoint and its implications for the functional role of hippocampal ACh in memory, we seek to promote the idea that data from lesions are compatible with data from other experimental approaches. Furthermore, we suggest that a convergent approach that incorporates observations from different experimental methods will reveal functional characteristics of hippocampal ACh that would not be apparent from studies using a single strategy.Before discussing the role of this system in cognition, a brief review of its anatomical and neurochemical organization is warranted. The septum is connected to the hippocampus via the fimbria-fornix, which carries projections ...

Selective septohippocampal – but not forebrain amygdalar – cholinergic dysfunction in diencephalic amnesia

“…This example exemplifies that the role of ACh in learning and memory is not a simple story [15,17,34,39]. A current theory is that the ACh level sets the appropriate physiological tone in the hippocampus (and potentially other structures) for learning and later memory as well as related neural adaptation [13,15,17].…”

“…However, our data suggest that when the hippocampus is dysfunctional, activation of the amygdala does not lead to behavioral recovery on a spatial exploration task without reward in the PTD model. Thus, given the demands of the task, level of training and integrity of the brain, amygdalar ACh response can vary to correlate with behavior or not.This example exemplifies that the role of ACh in learning and memory is not a simple story [15,17,34,39]. A current theory is that the ACh level sets the appropriate physiological tone in the hippocampus (and potentially other structures) for learning and later memory as well as related neural adaptation [13,15,17].…”

Transplantation of neural progenitors enhances production of endogenous cells in the impaired brain

“…[16][17][18][19][20][21][39][40][41] Both of these behavioral tests are affected by the cholinergic septohippocampal projection. [42][43][44] On the biochemical/molecular level, prenatal heroin induced both pre-and postsynaptic hyperactivity in the hippocampal cholinergic innervation, 16,17,23,45 converging on a total abolishment of the specific cholinergic-induced activation of PKCg. 16,21,41,46 This appears to be a major mechanism of these behavioral defects.…”

Lifelong environmental enrichment in rats: impact on emotional behavior, spatial memory vividness, and cholinergic neurons over the lifespan

“…This view was challenged as selective cholinergic lesions of the septal region did not affect water maze performance or produced only modest alterations (e.g., Baxter et al 1995). The persistence of a spatial memory, however, may be compromised when such lesions also affect the NBM (Parent and Baxter 2004;Traissard et al 2007). Thus, because the loss of basal forebrain cholinergic neurons occurred in both the septo-hippocampal and the basalo-cortical systems, its contribution to the age-related spatial memory impairments is well possible.…”