Corticostriatal mechanisms of action learning and habit formation

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Chronic THC Effects on Sleep and Behavioral Function Drugs derived from Cannabis sativa (e.g. marijuana, hashish) are known to promote sleep when taken acutely. However, studies in human volunteers indicate that disrupted sleep is observed following long-lasting, heavy use of these drugs. To determine the mechanisms underlying cannabis-induced sleep disruption we used a mouse model of chronic exposure to delta-9-tetrahydrocannabinol (THC) (the major psychoactive ingredient in cannabis derivatives) using a regimen known to produce tolerance to many effects of the compound. We performed polysomnographic recordings of sleep and sleep architecture in male mice using a fully automated system developed in our group. Mice were given 10 mg/kg doses of THC over several days. As expected, the first dose of THC promoted non-Rapid eye movement (NREM) sleep even during the dark cycle when mice are normally active. After a few days of treatment THC injection not longer induced this hypnogenic effect, indicating tolerance to this drug action. Over the first couple of days following the last THC injection mice showed fragmented NREM sleep, along with some changes in REM sleep. This sleep disruption returned to normal within 4 days following the last THC exposure. Injection of 1 mg/kg THC had little effect on sleep acutely, and no evidence of sleep disruption was observed following cessation of drug exposure at this dose. Interestingly, while female mice showed enhanced NREM sleep following the first THC dose they did not exhibit sleep disruption following the cessation of treatment after many days of exposure. It will be interesting to determine what mechanisms underlie this sex difference in sleep disruption during withdrawal from THC. We also examined effects of the chronic THC exposure on different reward and cognition-related behaviors. In a sucrose preference test, male mice treated chronically with THC showed reduced preference for sucrose during the first few days following cessation of drug treatment, while females showed no such reduction. Several other behavioral tests, such as novel object recognition, did not reveal any effect of chronic THC exposure in either male or female mice. Our findings may indicate a mild anhedonic effect of withdrawal from THC in the male mice. Ongoing experiments are examining other measures of decision making and cognitive function in the chronic THC-exposed mice. We are alto initiating experiments examining neurobiological mechanisms potentially impacted by acute and chronic THC treatment and their contributions to sleep disruption and other withdrawal-related behavioral changes. D2 Dopamine Receptors Expressed by Indirect Pathway Striatal Medium Spiny Neurons Contribute to Effort and Vigor of Action Production The neuromodulator dopamine contributes to brain mechanisms of salience, reward, action learning and action production. Loss of this key brain molecule produces hypomotility, as seen in Parkinson's Disease (PD). In the striatum, dopamine modulates neuronal activity through actions on several receptors distributed on different neuronal subtypes. The indirect pathway medium spiny projection neurons (iMSNs) express the majority of the D2 subtype of dopamine receptor. This receptor couples to the Gi/o-type G-protein, and the receptor has been shown to inhibit iMSN activity and reduce presynaptic GABA release from these neurons. To examine the contribution of iMSN D2 receptors to action control and learning, we bred mice in which the receptor was removed from iMSNs throughout the striatum. The large majority of D2 receptors were lost in these iMSN-D2KO mice, but previous studies indicated that D2 receptors on dopaminergic neurons and striatal cholinergic neurons were intact. The mice developed normally and were generally healthy. We examined instrumental lever-pressing, performance in a water-filled T-maze, pavlovian conditioning, performance on an accelerating rotatod (a form of skill learning) and Porsolt swim test performance in these mice compared to control littermates. The iMSN-D2KO mice readily learned to lever-press for food reward on a fixed ratio 1 schedule in the self-paced instrumental learning task. However, when task demand was increased by changing to a fixed ratio 5 schedule, the iMSN-D2KO mice showed slower lever pressing, decreased initiation of lever pressing and fewer rewards earned per session. The performance of these mice was not measurably different from controls in a single-session progressive ratio task, and they consumed as much food as their wild type littermates suggesting that their motivation for the food reward was unaffected by loss of the receptor. The iMSN-D2KO mice also showed reduced initiation of swimming in the water T-maze task, but learned to locate food reward as well as the littermate controls. These findings indicate deficits in action initiation and vigor in the iMSN-D2KO mice, with no observable learning or memory deficits in these tasks. The iMSN-D2KO mice showed a lack of improvement over several days of rotatod training. Their performance was similar to the littermate controls on day 1 of training, but did not improve as much over the subsequent training days. In all other behavioral tests, the iMSN-D2KO mice performance was similar to controls. Most notably, the mice readily learned a pavlovian association between tone and food presentation, although they were a bit slower to retrieve food than their littermate controls. Both groups of mice showed equivalent extinction of this pavlovian response. Overall, our findings indicate that the major role of iMSN D2 receptors is to invigorate action initiation and sustained production, particularly under conditions where enhanced effort is required for optimal performance. These findings are consistent with previous studies indicating decreased action production in these mice, and older studies implicating dopamine and D2 receptors in action invigoration. The loss of this D2 receptor signaling, that results in loss of a key brake on indirect pathway function, is likely an important component of the hypokinesia observed with dopamine depletion and in PD.