Biology subjects

Ramsey, L. A.

Publications and source records attributed to Ramsey, L. A..

4 recordsLinked to original sources

bioRxiv2026

Neuronal Grin2c expression and the cocaine engram: a medial prefrontal cortex substrate for conditioned place preference

Learned associations between drugs of abuse and drug-associated stimuli are thought to be encoded by physical alterations, termed engrams, within activity-dependent neuronal ensembles. However, the molecular mechanisms that support drug-memory engrams remain largely unknown. The goal of our study was to assess transcriptional alterations as candidate engrams within medial prefrontal cortex (mPFC) ensembles selectively activated by exposure to a cocaine-paired context following cocaine conditioned place preference (CPP). Using the immediate early gene Fos to identify strongly activated neurons, we found that mPFC was strongly activated by exposure to the cocaine-paired context, but not to the unpaired saline control context. We then used a combination of fluorescence activated cell sorting (FACS) and subsequent qPCR to identify gene targets upregulated in the Fos-positive mPFC ensemble neurons relative to the Fos-negative mPFC neurons following context re-exposure. Of the genes examined, the most strongly induced in the Fos-expressing neurons was Grin2c, which encodes the NR2C subunit of the NMDA receptor. We confirmed this finding using RNAscope in situ hybridization. To assess a causal role for Grin2c in cocaine-induced CPP, we used AAV-mediated, neuron-selective expression of Grin2c microRNA to knockdown Grin2c expression in mPFC neurons, which reduced cocaine CPP and facilitated CPP extinction over repeated tests. Our results indicate that neuronal Grin2c expression in the mPFC plays a role in associative learning underlying cocaine CPP. Future studies are needed to determine whether Grin2c expression plays a broader role within engrams underlying other forms of learning and memory.

neuroscience↗

bioRxiv2025

Distinct prelimbic cortex ensembles encode response execution and inhibition

Learning when to initiate or withhold actions is essential for survival and requires integration of past experiences with new information to adapt to changing environments. While stable prelimbic cortex (PL) ensembles have been identified during reward learning, it remains unclear how they adapt when contingencies shift. Does the same ensemble adjust its activity to support behavioral suppression upon reward omission, or is a distinct ensemble recruited for this new learning? We used single-cell calcium imaging to longitudinally track PL neurons in rats across operant food reward Training, Extinction and Reinstatement, trained rat-specific decoders to predict trial-wise behavior, and implemented an in-silico deletion approach to characterize ensemble contributions to behavior. We show that operant training and extinction recruit distinct PL ensembles that encode response execution and inhibition, and that both ensembles are re-engaged and maintain their roles during Reinstatement. These findings highlight ensemble-based encoding of multiple learned associations within a region, with selective ensemble recruitment supporting behavioral flexibility under changing contingencies.

neuroscience↗

bioRxiv2020

Medial Prefrontal Cortex Interacts with the Anteromedial Thalamus in Motivation and Dopaminergic Activity

How does the prefrontal cortex (PFC) regulate motivated behavior? Our experiments characterize the circuits of the PFC regulating motivation, reinforcement and dopamine activity, revealing a novel cortico-thalamic loop. The stimulation of medial PFC (mPFC) neurons activated many downstream regions, as shown by functional MRI. Axonal terminal stimulation of mPFC neurons in downstream regions, including the anteromedial thalamic nucleus (AM), reinforced behavior and activated midbrain dopaminergic neurons. The stimulation of AM neurons projecting to the mPFC also reinforced behavior and activated dopamine neurons, and mPFC and AM showed a positive-feedback loop organization. Reciprocal excitatory functional connectivity, as well as co-activation of the two regions, was found in human participants who watched reinforcing videos. Our results suggest that this cortico-thalamic loop regulates motivation, reinforcement and dopaminergic neuron activity.

neuroscience↗

bioRxiv2020

Supramammillary neurons projecting to the septum regulate dopamine and motivation for environmental interaction

The supramammillary region (SuM) is a posterior hypothalamic structure, known to regulate hippocampal theta oscillations and arousal. However, recent studies reported that the stimulation of SuM neurons with neuroactive chemicals, including substances of abuse, is reinforcing. We conducted experiments to illuminate how SuM neurons mediate such effects. The excitation of SuM glutamatergic (GLU) neurons was reinforcing in mice; this effect was relayed by the projections to septal GLU neurons. SuM neurons were active during exploration and approach behavior and diminished activity during sucrose consumption. Consistently, inhibition of SuM neurons disrupted approach responses, but not sucrose consumption. Such functions are similar to those of mesolimbic dopamine neurons. Indeed, the stimulation of SuM-to-septum GLU neurons and septum-to-ventral tegmental area (VTA) GLU neurons activated mesolimbic dopamine neurons. We propose that the supramammillo-septo-VTA pathway is important in reinforcement and approach motivation and may play an important role in mood and substance-use disorders.

neuroscience↗