Interactions between Procedural Learning and Cocaine Exposure Alter Spontaneous and Cortically Evoked Spike Activity in the Dorsal Striatum

We have previously shown that cocaine enhances gene regulation in the sensorimotor striatum associated with procedural learning in a running-wheel paradigm. Here we assessed whether cocaine produces enduring modifications of learning-related changes in striatal neuron activity, using single-unit recordings in anesthetized rats 1 day after the wheel training. Spontaneous and cortically evoked spike activity was compared between groups treated with cocaine or vehicle immediately prior to the running-wheel training or placement in a locked wheel (control conditions). We found that wheel training in vehicle-treated rats increased the average firing rate of spontaneously active neurons without changing the relative proportion of active to quiescent cells. In contrast, in rats trained under the influence of cocaine, the proportion of spontaneously firing to quiescent cells was significantly greater than in vehicle-treated, trained rats. However, this effect was associated with a lower average firing rate in these spontaneously active cells, suggesting that training under the influence of cocaine recruited additional low-firing cells. Measures of cortically evoked activity revealed a second interaction between cocaine treatment and wheel training, namely, a cocaine-induced decrease in spike onset latency in control rats (locked wheel). This facilitatory effect of cocaine was abolished when rats trained in the running wheel during cocaine action. These findings highlight important interactions between cocaine and procedural learning, which act to modify population firing activity and the responsiveness of striatal neurons to excitatory inputs. Moreover, these effects were found 24 h after the training and last drug exposure indicating that cocaine exposure during the learning phase triggers long-lasting changes in synaptic plasticity in the dorsal striatum. Such changes may contribute to the transition from recreational to habitual or compulsive drug taking behavior

Imbalanced decision hierarchy in addicts emerging from drug-hijacked dopamine spiraling circuit

Despite explicitly wanting to quit, long-term addicts find themselves powerless to resist drugs, despite knowing that drug-taking may be a harmful course of action. Such inconsistency between the explicit knowledge of negative consequences and the compulsive behavioral patterns represents a cognitive/behavioral conflict that is a central characteristic of addiction. Neurobiologically, differential cue-induced activity in distinct striatal subregions, as well as the dopamine connectivity spiraling from ventral striatal regions to the dorsal regions, play critical roles in compulsive drug seeking. However, the functional mechanism that integrates these neuropharmacological observations with the above-mentioned cognitive/behavioral conflict is unknown. Here we provide a formal computational explanation for the drug-induced cognitive inconsistency that is apparent in the addicts' “self-described mistake”. We show that addictive drugs gradually produce a motivational bias toward drug-seeking at low-level habitual decision processes, despite the low abstract cognitive valuation of this behavior. This pathology emerges within the hierarchical reinforcement learning framework when chronic exposure to the drug pharmacologically produces pathologicaly persistent phasic dopamine signals. Thereby the drug hijacks the dopaminergic spirals that cascade the reinforcement signals down the ventro-dorsal cortico-striatal hierarchy. Neurobiologically, our theory accounts for rapid development of drug cue-elicited dopamine efflux in the ventral striatum and a delayed response in the dorsal striatum. Our theory also shows how this response pattern depends critically on the dopamine spiraling circuitry. Behaviorally, our framework explains gradual insensitivity of drug-seeking to drug-associated punishments, the blocking phenomenon for drug outcomes, and the persistent preference for drugs over natural rewards by addicts. The model suggests testable predictions and beyond that, sets the stage for a view of addiction as a pathology of hierarchical decision-making processes. This view is complementary to the traditional interpretation of addiction as interaction between habitual and goal-directed decision systems

Age-related effects on the association between alcohol use, severity and resting-state fMRI:a rat study comparing adolescent-onset and adult-onset drinking

Adolescence is marked by neurodevelopmental changes that increase reward sensitivity, risk-taking, and behavioural control challenges, heightening the risk of alcohol use and dependence. Alcohol's impact on resting-state functional connectivity (RSFC) may explain this risk, though comparisons to adulthood remain limited. This study examined age-related differences in the association between RSFC and alcohol use severity in rats that initiated low or high voluntary alcohol consumption during adolescence or adulthood. Forty-two male rats were selected based on their alcohol consumption levels after two months of exposure: adolescent (PND42) onset low (N=12) and high drinking (N=7) rats, and adult (PND77) onset low (N=11) and high drinking (N=12) rats. RSFC was measured 4-10 days after exposure ceased, and group-ICA identified networks. Permutation tests assessed associations between onset age and use severity on RSFC. Low drinking was associated with increased RSFC within the salience network compared to high drinking. High adolescent onset alcohol consumption was associated with increased Default Mode Network (DMN) connectivity relative to low use. Connectivity in this area was generally stronger in adult compared to adolescent onset groups. An age group effect was observed, with overall higher DMN-thalamic connectivity in adult versus adolescent onset rats. In conclusion, high adolescent alcohol use was associated with increased DMN connectivity compared to low use, potentially reflecting altered self-referential processing or withdrawal susceptibility in adulthood. In adult-onset rats, the observed increases in DMN and DMN-thalamic connectivity may reflect developmental differences rather than alcohol exposure. These findings highlight the need for further research on DMN connectivity and its role in AUD risk and resilience, particularly regarding adolescent alcohol use, and the inclusion of a control group without alcohol access to better isolate the effects of alcohol consumption.</p

The direct and indirect pathways of the basal ganglia antagonistically influence cortical activity and perceptual decisions

The striatum, the main input nucleus of the basal ganglia, receives topographically organized input from the cortex and gives rise to the direct and indirect output pathways, which have antagonistic effects on basal ganglia output directed to the cortex. We optogenetically stimulated the direct and indirect pathways in a visual and a working memory task in mice that responded by licking. Unilateral direct pathway stimulation increased the probability of lick responses toward the contralateral, non-stimulated side and increased cortical activity globally. In contrast, indirect pathway stimulation increased the probability of responses toward the stimulated side and decreased activity in the stimulated hemisphere. Moreover, direct pathway stimulation enhanced the neural representation of a contralateral visual stimulus during the delay of the working memory task, whereas indirect pathway stimulation had the opposite effect. Our results demonstrate how these two pathways influence perceptual decisions and working memory and modify activity in the dorsal cortex

NINscope, a versatile miniscope for multi-region circuit investigations

Miniaturized fluorescence microscopes (miniscopes) have been instrumental to monitor neural signals during unrestrained behavior and their open-source versions have made them affordable. Often, the footprint and weight of open-source miniscopes is sacrificed for added functionality. Here, we present NINscope: a light-weight miniscope with a small footprint that integrates a high-sensitivity image sensor, an inertial measurement unit and an LED driver for an external optogenetic probe. We use it to perform the first concurrent cellular resolution recordings from cerebellum and cerebral cortex in unrestrained mice, demonstrate its optogenetic stimulation capabilities to examine cerebello-cerebral or cortico-striatal connectivity, and replicate findings of action encoding in dorsal striatum. In combination with cross-platform acquisition and control software, our miniscope is a versatile addition to the expanding tool chest of open-source miniscopes that will increase access to multi-region circuit investigations during unrestrained behavior

Changes in Striatal Dopamine Release Associated with Human Motor-Skill Acquisition

The acquisition of new motor skills is essential throughout daily life and involves the processes of learning new motor sequence and encoding elementary aspects of new movement. Although previous animal studies have suggested a functional importance for striatal dopamine release in the learning of new motor sequence, its role in encoding elementary aspects of new movement has not yet been investigated. To elucidate this, we investigated changes in striatal dopamine levels during initial skill-training (Day 1) compared with acquired conditions (Day 2) using 11C-raclopride positron-emission tomography. Ten volunteers learned to perform brisk contractions using their non-dominant left thumbs with the aid of visual feedback. On Day 1, the mean acceleration of each session was improved through repeated training sessions until performance neared asymptotic levels, while improved motor performance was retained from the beginning on Day 2. The 11C-raclopride binding potential (BP) in the right putamen was reduced during initial skill-training compared with under acquired conditions. Moreover, voxel-wise analysis revealed that 11C-raclopride BP was particularly reduced in the right antero-dorsal to the lateral part of the putamen. Based on findings from previous fMRI studies that show a gradual shift of activation within the striatum during the initial processing of motor learning, striatal dopamine may play a role in the dynamic cortico-striatal activation during encoding of new motor memory in skill acquisition

The continued need for animals to advance brain research

Policymakers aim to move toward animal-free alternatives for scientific research and have introduced very strict regulations for animal research. We argue that, for neuroscience research, until viable and translational alternatives become available and the value of these alternatives has been proven, the use of animals should not be compromised

Intra-Accumbens Injection of a Dopamine Aptamer Abates MK-801-Induced Cognitive Dysfunction in a Model of Schizophrenia

Systemic administration of the noncompetitive NMDA-receptor antagonist, MK-801, has been proposed to model cognitive deficits similar to those seen in patients with schizophrenia. The present work investigated the ability of a dopamine-binding DNA aptamer to regulate these MK-801-induced cognitive deficits when injected into the nucleus accumbens. Rats were trained to bar press for chocolate pellet rewards then randomly assigned to receive an intra-accumbens injection of a DNA aptamer (200 nM; n = 7), tris buffer (n = 6) or a randomized DNA oligonucleotide (n = 7). Animals were then treated systemically with MK-801 (0.1 mg/kg) and tested for their ability to extinguish their bar pressing response. Two control groups were also included that did not receive MK-801. Data revealed that injection of Tris buffer or the random oligonucleotide sequence into the nucleus accumbens prior to treatment with MK-801 did not reduce the MK-801-induced extinction deficit. Animals continued to press at a high rate over the entire course of the extinction session. Injection of the dopamine aptamer reversed this MK-801-induced elevation in lever pressing to levels as seen in rats not treated with MK-801. Tests for activity showed that the aptamer did not impair locomotor activity. Results demonstrate the in vivo utility of DNA aptamers as tools to investigate neurobiological processes in preclinical animal models of mental health disease