Biology subjects

Clem, R.

Publications and source records attributed to Clem, R..

4 recordsLinked to original sources

bioRxiv2023

The mouse dorsal peduncular cortex encodes fear memory

The rodent medial prefrontal cortex (mPFC) is a locus for both the promotion and suppression (e.g. extinction) of fear and is composed of four anatomically distinct subregions, including anterior cingulate 1 (Cg1), prelimbic (PL), infralimbic (IL), and the dorsal peduncular (DP) cortex. A vast majority of studies have focused on Cg1, PL, and IL. The Cg1 and PL have been implicated in the promotion of fear, while the IL has been linked to a role in the suppression, or extinction, of fear. Due to its anatomical location ventral to IL, the DP has been hypothesized to function as a fear-suppressing brain region however, no studies have explicitly tested its role in this function or in the regulation of memory generally. Moreover, some studies have pointed towards a dichotomous role for ventral mPFC in the dual suppression and promotion of fear, but the mechanisms underlying these opposing observations remains unclear. Here, we provide evidence that the DP paradoxically functions as a cued fear-encoding brain region and plays little to no role in fear memory extinction. By using a combination of cFos immunohistochemistry, whole-cell brain slice electrophysiology, fiber photometry, and activity-dependent neural tagging, we demonstrate that DP neurons exhibit learning-related plasticity, acquire cue-associated activity across learning and memory retrieval, and that DP neurons activated by learning are preferentially reactivated upon fear memory retrieval. Further, optogenetic activation and silencing of fear learning-related DP neural ensembles drives the promotion and suppression of freezing, respectively. Overall, these data suggest that the DP plays an unexpected role in fear memory encoding. More broadly, our results reveal new principles of organization across the dorsoventral axis of the mPFC.

neuroscience↗

bioRxiv2022

CRF Neurons Establish Resilience via Stress-History-Dependent BNST Modulation

IntroductionCumulative stress is a major risk factor for developing major depressive disorder (MDD), yet not everyone experiencing chronic stress develops MDD. In those who do not, it is unclear at what point, or by what mechanism, a trajectory of stable resiliency emerges. MethodsUtilizing a 10-day repeated social defeat stress model (RSDS) for MDD, we observed that a critical period between 7 and 10 daily defeats marks the phenotypical divergence of resilient from susceptible mice. Using cell-type selective electrophysiology, chemogenetics, optogenetics, fiber photometry and RNA quantification was employed to investigate the nature of stress effects on neuroadaptation in the oval nucleus of the bed nucleus of the stria terminalis (BNSTov) required to determine resilience. ResultsIn response to ongoing stress, corticotropin-releasing factor (CRF+, but not CRF-) neurons of the (BNSTov) displayed a sustained increased firing rate in resilient, but not susceptible mice. This neurophysiological adaptation was self-sustaining, but only after 7 critical stress exposures, indicating that the process of developing resilience is dependent on stress history. ConclusionOur study reveals a novel process by which individuals might persist in the face of adversity by way of stress-provoked activation, not inhibition of a key CRF limbic region that establishes a pathway to resilience.

neuroscience↗

bioRxiv2022

Ensemble-specific deficit in neuronal intrinsic excitability in aged mice

With the prevalence of age-related cognitive deficits on the rise, it is essential to identify cellular and circuit alterations that contribute to age-related memory impairment. Increased intrinsic neuronal excitability after learning is important for memory consolidation, and changes to this process could underlie memory impairment in old age. Some studies find age-related deficits in hippocampal neuronal excitability that correlate with memory impairment but others do not, possibly due to selective changes only in activated neural ensembles. Thus, we tagged CA1 neurons activated during learning and recorded their intrinsic excitability 5 hours or 7 days post-training. Adult mice exhibited increased neuronal excitability 5 hours after learning, specifically in ensemble (learning-activated) CA1 neurons. As expected, ensemble excitability returned to baseline 7 days post-training. In aged mice, there was no ensemble-specific excitability increase after learning, which was associated with impaired hippocampal memory performance. These results suggest that CA1 may be susceptible to age-related impairments in post-learning ensemble excitability and underscore the need to selectively measure ensemble-specific changes in the brain.

neuroscience↗

bioRxiv2019

Orexin signaling in GABAergic lateral habenula neurons modulates aggressive behavior

Heightened aggression is characteristic of multiple neuropsychiatric disorders and can have a wide variety of negative effects on patients, their families, and the public. Recent studies in humans and animals have implicated brain reward circuits in aggression and suggest that, in subsets of aggressive individuals, repeated domination of subordinate social targets is reinforcing. Here, we show that orexin neurons originating from the lateral hypothalamus activate a small population of GABAergic interneurons in the lateral habenula (LHb) via orexin receptor 2 (OxR2) to promote aggression and conditioned place preference (CPP) for aggression-paired contexts. Our study suggests that the orexin system is a potential target for the development of novel therapies aimed at reducing aggressive behaviors and provides the first functional evidence of a local inhibitory circuit within the LHb.

neuroscience↗