Biology subjects

Carroll-Deaton, J.

Publications and source records attributed to Carroll-Deaton, J..

3 recordsLinked to original sources

bioRxiv2024

Enhanced Fear Extinction Through Infralimbic Perineuronal Net Digestion: The Modulatory Role of Adolescent Alcohol Exposure

Perineuronal nets (PNNs) are specialized components of the extracellular matrix that play a critical role in learning and memory. In a Pavlovian fear conditioning paradigm, degradation of PNNs affects the formation and storage of fear memories. This study examined the impact of adolescent intermittent ethanol (AIE) exposure by vapor inhalation on the expression of PNNs in the adult rat prelimbic (PrL) and infralimbic (IfL) subregions of the medial prefrontal cortex. Results indicated that following AIE, the total number of PNN positive cells in the PrL cortex increased in layer II/III but did not change in layer V. Conversely, in the IfL cortex, the number of PNN positive cells decreased in layer V, with no change in layer II/III. In addition, the intensity of PNN staining was significantly altered by AIE exposure, which narrowed the distribution of signal intensity, reducing the number of high and low intensity PNNs. Given these changes in PNNs, the next experiment assessed the effects of AIE and PNN digestion on extinction of a conditioned fear memory. In Air control rats, digestion of PNNs by bilateral infusion of Chondroitinase ABC (ChABC) into the IfL cortex enhanced fear extinction and reduced contextual fear renewal. In contrast, both fear extinction learning and contextual fear renewal remained unchanged following PNN digestion in AIE exposed rats. These results highlight the sensitivity of prefrontal PNNs to adolescent alcohol exposure and suggest that ChABC-induced plasticity is reduced in the IfL cortex following AIE exposure.

neuroscience↗

bioRxiv2024

Corticostriatal ensemble dynamics across heroin self-administration to reinstatement

Corticostriatal projection neurons from prelimbic medial prefrontal cortex to the nucleus accumbens core critically regulate drug-seeking behaviors, yet the underlying encoding dynamics whereby these neurons contribute to drug seeking remain elusive. Here we use two-photon calcium imaging to visualize the activity of corticostriatal neurons in mice from the onset of heroin use to relapse. We find that the activity of these neurons is highly heterogeneous during heroin self-administration and seeking, with at least 8 distinct neuronal ensembles that display both excitatory and inhibitory encoding dynamics. These neuronal ensembles are particularly apparent during relapse, where excitatory responses are amplified compared to heroin self-administration. Moreover, we find that optogenetic inhibition of corticostriatal projection neurons attenuates heroin seeking regardless of the relapse trigger. Our results reveal the precise corticostriatal activity dynamics underlying drug-seeking behaviors and support a key role for this circuit in mediating relapse to drug seeking.

neuroscience↗

bioRxiv2024

Accumbens Nitrergic Interneurons Drive the Cell Type-Specific Synaptic Plasticity Required for Cue-Induced Cocaine Seeking

Cocaine use disorder (CUD) remains a serious public health crisis, with relapse vulnerability continuing to pose the largest impediment to effective clinical treatment. Relapse to cocaine seeking is often triggered by drug craving evoked by exposure to drug-associated environmental cues. Data from preclinical models of rodent self-administration (SA) and cue-induced reinstatement demonstrate that exposure to drug predictive cues following a period of withdrawal engages a large induction of glutamate release in the nucleus accumbens core (NAc), not observed during cued sucrose seeking. This profound glutamate release engages neuronal nitric oxide synthase (nNOS) expressing interneurons likely through activation of metabotropic glutamate receptor 5 (mGluR5), leading to increased production of nitric oxide (NO). Importantly, cue-induced glutamate and NO production have been linked to activation of matrix metalloproteinases (MMPs) and induction of the transient synaptic plasticity in medium spiny neurons (MSNs) required for cued cocaine seeking. Recent evidence suggests that cue-induced structural and synaptic plasticity occurs predominantly in D1 Dopamine receptor expressing MSNs, yet despite these findings, how cue-induced glutamate release is translated into D1 MSN plasticity has yet to be elucidated. We show here that knockdown of nNOS is sufficient to block cue-induced reinstatement to cocaine and prevents cue-induced functional and structural synaptic adaptions specifically in D1 receptor containing MSNs. Next, we demonstrate that knockdown of mGluR5, selectively on nitrergic interneurons in the NAc, is sufficient to block both conditioned place preference (CPP) and cue-induced reinstatement to cocaine, mechanistically linking cue-associated glutamate release to NO signaling. Finally, we demonstrate that downstream of glutamate-mediated activation of mGluR5 on nitrergic interneurons and MMP activation, expression of {beta}3 integrin receptors on D1 MSNs is required for cued cocaine seeking. Taken together, our data provide a mechanistic link between cocaine cue-induced glutamate release, activation of nitrergic interneurons and the D1 MSN plasticity required for cued cocaine seeking, Significance StatementRelapse vulnerability to cocaine is a persistent challenge to successful treatment of CUD. Relapse precipitated by drug-associated environment cues requires synaptic plasticity in MSNs. Here, we show that knockdown of nNOS, or mGluR5 on nitrergic interneurons, or {beta}3 integrin receptors on D1 MSNs is sufficient to block cue-induced cocaine seeking. Taken together our data support the following cocaine seeking signaling cascade. {square}Cocaine cues [->] PrL driven NAc glutamate release [->] mGluR5-mediated Activation of NAc nitrergic neurons [->] Activation of B3 integrins [->] D1 MSN plasticity [->] Reinstated Cocaine seeking.

neuroscience↗