Biology subjects

McGinty, J. F.

Publications and source records attributed to McGinty, J. F..

5 recordsLinked to original sources

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↗

bioRxiv2024

Vagus nerve stimulation (VNS) modulates synaptic plasticity in the rat infralimbic cortex via Trk-B receptor activation to reduce drug-seeking

Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drug-seeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces relapse. Vagus nerve stimulation (VNS) has previously been shown to enhance extinction learning and reduce drug-seeking. Here we determined the effects of VNS-mediated release of brain-derived neurotrophic factor (BDNF) on extinction and cue-induced reinstatement in rats trained to self-administer cocaine. Pairing 10 days of extinction training with VNS facilitated extinction and reduced drug-seeking behavior during reinstatement. Rats that received a single extinction session with VNS showed elevated BDNF levels in the medial PFC as determined via an enzyme-linked immunosorbent assay (ELISA). Systemic blockade of Tropomyosin receptor kinase B (TrkB) receptors during extinction, via the TrkB antagonist ANA-12, decreased the effects of VNS on extinction and reinstatement. Whole-cell recordings in brain slices showed that cocaine self-administration induced alterations in the ratio of AMPA and NMDA receptor-mediated currents in layer 5 pyramidal neurons of the infralimbic cortex (IL). Pairing extinction with VNS reversed cocaine-induced changes in glutamatergic transmission by enhancing AMPAR currents, and this effect was blocked by ANA-12. Our study suggests that VNS consolidates extinction of drug-seeking behavior by reversing drug-induced changes in synaptic AMPA receptors in the IL, and this effect is abolished by blocking TrkB receptors during extinction, highlighting a potential mechanism for the therapeutic effects of VNS in addiction. Significance StatementExtinction training can reverse maladaptive neuroplasticity induced by drugs of abuse, but adjunct treatments are sought that can facilitate the process and consolidate the newly formed memories. Pairing extinction training with vagus nerve stimulation (VNS) facilitates extinction and reduces drug-seeking behavior during reinstatement. Here, we show that rats receiving a single extinction session with VNS exhibit elevated brain-derived neurotrophic factor (BDNF) levels in the medial prefrontal cortex (mPFC). We also demonstrate that VNS consolidates the extinction of drug-seeking behavior by reversing cocaine-induced changes in synaptic AMPA receptors in the infralimbic cortex (IL) of the mPFC. This effect is blocked by the TrkB antagonist ANA-12, emphasizing the role of BDNF and TrkB receptors in the therapeutic effects of VNS in addiction.

neuroscience↗

bioRxiv2020

Heroin self-administration and extinction increases prelimbic cortical astroglia-synapse proximity and alters dendritic spine morphometrics that are reversed by N-acetylcysteine

Clinical and preclinical studies indicate that adaptations in corticostriatal neurotransmission significantly contribute to heroin relapse vulnerability. In animal models, heroin self-administration and extinction produce cellular adaptations in both neurons and astrocytes within the nucleus accumbens (NA) core that are required for cue-induced heroin seeking. Specifically, decreased glutamate clearance and reduced association of perisynaptic astrocytic processes with NAcore synapses allow glutamate release from prelimbic (PrL) cortical terminals to engage synaptic and structural plasticity in NAcore medium spiny neurons. Normalizing astroglial glutamate homeostasis with drugs like the antioxidant N-acetylcysteine (NAC) prevents cue-induced heroin seeking. Surprisingly, little is known about heroin-induced alterations in astrocytes or pyramidal neurons projecting to the NAcore in the PrL cortex (PrL-NAcore). Here, we observed increased complexity of the glial fibrillary acidic protein (GFAP) cytoskeletal arbor and increased association of the astroglial plasma membrane with synaptic markers following heroin SA and extinction training in the PrL cortex. Repeated treatment with NAC during extinction reversed both the enhanced astroglial complexity and synaptic association. In PrL-NAcore neurons, heroin SA and extinction decreased apical tuft dendritic spine density and enlarged dendritic spine head diameter in male Sprague-Dawley rats. Repeated NAC treatment during extinction prevented decreases in spine density but not dendritic spine head expansion. Moreover, heroin SA and extinction increased co-registry of the GluA1 subunit of AMPA receptors in both the dendrite shaft and spine heads of PrL-NAcore neurons. Interestingly, accumulation of GluA1 immunoreactivity in spine heads was further potentiated by NAC treatment during extinction. Taken together, our data reveal circuit-level adaptations in cortical dendritic spine morphology potentially linked to heroin-induced alterations in astrocyte complexity and association at synapses. Additionally, these data demonstrate, for the first time, that NAC reverses PrL cortical heroin SA and extinction-induced adaptations in both astrocytes and corticostriatal neurons.

neuroscience↗

bioRxiv2018

Cocaine Self-Administration and Time-dependent Decreases in Prelimbic Activity

Cocaine self-administration causes dephosphorylation of proteins in prelimbic (PL) cortex that mediate excitation-transcription coupling, suggesting that cocaine causes decreased activity in PL neurons. Thus, we used in vivo single-unit extracellular recordings in awake, behaving rats to measure activity in PL neurons before, during, and after cocaine self-administration on the first and last session day (range 12-14 days). On the last day, cocaine suppressed 52% of recorded neurons in the PL cortex when compared to a 20 min baseline, significantly more than the 23% of neurons suppressed on the first day of cocaine. There was no change in the percentage of neurons that were excited on the first vs. the last day of self-administration (14% vs. 13%, respectively). To determine whether the tonic inhibitory shift was induced by the behavior or by the drug itself, rats received a final session in which cocaine availability was delayed for the first 30 min or in which cocaine was administered non-contingently in the absence of levers or cues in a subset of rats. These manipulations indicated that cocaine was both necessary and sufficient to induce a downshift in PL neuronal activity. However, this activity decrease was not observed in rats that received only non-contingent cocaine for 12-14 days, indicating that contingency during self-administration training contributes to the cocaine-induced tonic downshift in PL activity. These data suggest that the session-by-session decrease in PL neuronal activity induced by cocaine is a reflection of learned drug-seeking behavior and, hence, reducing this inhibition may lessen cocaine addiction.

neuroscience↗