Top-down control of hippocampal signal-to-noise by prefrontal long-range inhibition

Abstract

The prefrontal cortex (PFC) is postulated to exert 'top-down control' by modulating information processing throughout the brain to promote specific actions based on current goals. However, the pathways mediating top-down control remain poorly understood. In particular, knowledge about direct prefrontal connections that might facilitate top-down prefrontal control of information processing in the hippocampus remains sparse. Here we describe novel monosynaptic long-range GABAergic projections from PFC to hippocampus. These preferentially inhibit vasoactive intestinal polypeptide expressing interneurons, which are known to disinhibit hippocampal microcircuits. Indeed, stimulating prefrontal−hippocampal GABAergic projections increases hippocampal feedforward inhibition and reduces hippocampal activity in vivo. The net effect of these actions is to specifically enhance the signal-to-noise ratio for hippocampal representations of objects. Correspondingly, stimulation of PFC-to-hippocampus GABAergic projections promotes object exploration. Together, these results elucidate a novel top-down pathway in which long-range GABAergic projections target disinhibitory microcircuits, thereby enhancing signals and network dynamics underlying exploratory behavior.

Control of Parallel Hippocampal Output Pathways by Amygdalar Long-Range Inhibition

“…In particular whether a role in motivated behaviour and place preference was specific to BA input, or due to the dorso-ventral location of this input in hippocampus. Interestingly, long range inhibition from entorhinal cortex, septum and PFC all preferentially target interneurons and avoid pyramidal neurons (Basu et al, 2016;Malik et al, 2021;Melzer et al, 2012;Schlesiger et al, 2021). In contrast our data shows that BA long range inhibition connects with both interneurons and pyramidal neurons (Figure 3), similar to that seen in long range inhibitory projections from BA to PFC (Seo et al, 2016).…”

“…For example, functional inhibitory projections from PFC to NAc (A. T. Lee et al, 2014), and BA to PFC (Seo et al, 2016) have both been shown to modulate value-based and reward behaviour, including the support of real time place preference and aversion. The hippocampus also receives long range inhibitory input from numerous regions including entorhinal cortex (Basu et al, 2016; Melzer et al, 2012), septum (Schlesiger et al, 2021) and PFC (Malik et al, 2021). While these studies focussed on dorsal hippocampal circuitry and a role for these projections in memory and navigation, due to the known dichotomy between dorsal and ventral hippocampal function (Fanselow and Dong, 2010; Strange et al, 2014), it would be interesting to investigate the presence and function of such long range inhibitory projections into vH.…”

“…There is enormous diversity of interneuron types throughout the hippocampus (Group et al, 2008), each of which involved in distinct parts of the circuit calculation – such as dendritic targeting SOM- and VIP-expressing neurons, perisomatic PV-expressing interneurons, and cholecystokinin- (CCK) expressing interneurons. Inhibitory input from entorhinal cortex preferentially innervates CCK interneurons (Basu et al, 2016), while input from PFC specifically innervates VIP interneurons (Malik et al, 2021). Thus, how BA input differentially innervates these populations is an important and interesting future question.…”

Coding of social odors in the hippocampal CA2 region as a substrate for social memory

“…A potential mechanism for the increased inhibition is suggested by a recent report describing a powerful direct top-down control of hippocampus by prefrontal cortex, via a specific subset of inhibitory long-range projection neurons. These projections preferentially inhibit vasoactive intestinal polypeptide expressing interneurons in the hippocampus, which result in disinhibition of hippocampal interneurons mediating feed-forward inhibition, leading to a net increase in inhibitory drive onto hippocampal pyramidal cells (Malik et al, 2021). The connection between prefrontal cortex and hippocampus is interesting in light of the finding that prefrontal cortex neurons of mice can form distinct representations of urine pooled from either several male or female conspecifics, although whether prefrontal cortex can encode representations of specific individual social odors remains to be determined (Levy et al, 2019).…”

Dual projecting cells linking thalamic and cortical communication routes between the medial prefrontal cortex and hippocampus

“…The HC, a core memory structure in the brain, has strong projections to mPFC with very few direct return projections from mPFC. In fact, return projections were only recently described by Malik et al, (2021) as a population of direct GABAergic projections from mPFC to inhibitory vasoactive intestinal polypeptide (VIP) interneurons in dorsal HC. Most mPFC communication with HC is polysynaptic.…”