Loss of control over harmful drug seeking is one of the most intractable aspects of addiction, as human substance abusers continue to pursue drugs despite incurring significant negative consequences. Human studies have suggested that deficits in prefrontal cortical function and consequential loss of inhibitory control could be crucial in promoting compulsive drug use. However, it remains unknown whether chronic drug use compromises cortical activity and, equally important, whether this deficit promotes compulsive cocaine seeking. Here we use a rat model of compulsive drug seeking in which cocaine seeking persists in a subgroup of rats despite delivery of noxious foot shocks. We show that prolonged cocaine self-administration decreases ex vivo intrinsic excitability of deep-layer pyramidal neurons in the prelimbic cortex, which was significantly more pronounced in compulsive drug-seeking animals. Furthermore, compensating for hypoactive prelimbic cortex neurons with in vivo optogenetic prelimbic cortex stimulation significantly prevented compulsive cocaine seeking, whereas optogenetic prelimbic cortex inhibition significantly increased compulsive cocaine seeking. Our results show a marked reduction in prelimbic cortex excitability in compulsive cocaine-seeking rats, and that in vivo optogenetic prelimbic cortex stimulation decreased compulsive drug-seeking behaviours. Thus, targeted stimulation of the prefrontal cortex could serve as a promising therapy for treating compulsive drug use.

Loss of dopamine is associated with increased synchronization and oscillatory activity in the subthalamic nucleus and basal ganglia (BG) output nuclei in both Parkinson's disease (PD) patients and animal models of PD. We have previously observed substantial increases in spectral power in the 25-40 Hz range in LFPs recorded in the substantia nigra pars reticulata (SNpr) and motor cortex (MCx) in the hemiparkinsonian rat during treadmill walking. The current study explores the hypothesis that SNpr output entrains activity in the ventral medial thalamus (VM) in this frequency range after loss of dopamine, which in turn contributes to entrainment of the MCx and BG. Electrode bundles were implanted in MCx, SNpr, and VM of rats with unilateral dopamine cell lesions. Spiking and LFP activity were recorded during epochs of rest and walking on a circular treadmill. After dopamine cell lesion, 30 -36 Hz LFP activity in the VM became more robust during treadmill walking and more coherent with LFP activity in the same range in MCx and SNpr. Infusion of the GABA A antagonist picrotoxin into the VM reduced both high beta power in MCx and SNpr and coherence between MCx and SNpr while temporarily restoring walking ability. Infusion of the GABA A agonist muscimol into the VM also reduced MCx-SNpr coherence and beta power but failed to improve walking. These results support the view that synchronized neuronal activity in the VM contributes to the emergence of high beta oscillations throughout the BG-thalamocortical network in the behaving parkinsonian rat.

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SummaryLateral intraparietal (LIP) neurons represent formation of perceptual decisions involving eye movements. In circuit models for these decisions, neural ensembles that encode actions compete to form decisions. Consequently, decision variables (DVs) are represented as partially potentiated action plans, where ensembles increase their average responses for stronger evidence supporting their preferred actions. As another consequence, DV representation and readout are implemented similarly for decisions with identical competing actions, irrespective of input and task context differences. Here, we challenge those core principles using a novel face-discrimination task, where LIP firing rates decrease with supporting evidence, contrary to conventional motion-discrimination tasks. These opposite response patterns arise from similar mechanisms in which decisions form along curved population-response manifolds misaligned with action representations. These manifolds rotate in state space based on task context, necessitating distinct readouts. We show similar manifolds in lateral and medial prefrontal cortices, suggesting a ubiquitous representational geometry across decision-making circuits.