SUMMARY A striking neurochemical form of compartmentalization has been found in the striatum of humans and other species, dividing it into striosomes and matrix. The function of this organization has been unclear, but the anatomical connections of striosomes indicate their relation to emotion-related brain regions including the medial prefrontal cortex. We capitalized on this fact by combining pathway-specific optogenetics and electrophysiology in behaving rats to search for selective functions of striosomes. We demonstrate that a medial prefronto-striosomal circuit is selectively active in and causally necessary for cost-benefit decision-making under approach-avoidance conflict conditions known to evoke anxiety in humans. We show that this circuit has unique dynamic properties likely reflecting striatal interneuron function. These findings demonstrate that cognitive and emotion-related functions are, like sensory-motor processing, subject to encoding within compartmentally organized representations in the forebrain, and suggest that striosome-targeting corticostriatal circuits can underlie neural processing of decisions fundamental for survival.

SUMMARY Effective evaluation of costs and benefits is a core survival capacity that in humans is considered as optimal, ’rational’ decision-making. This capacity is vulnerable in neuropsychiatric disorders and in the aftermath of chronic stress, in which aberrant choices and high-risk behaviors occur. We report that chronic stress exposure in rodents produces abnormal evaluation of costs and benefits resembling non-optimal decision-making in which choices of high-cost/high-reward options are sharply increased. Concomitantly, alterations in the task-related spike activity of medial prefrontal neurons correspond to increased activity of their striosome-predominant striatal projection neuron targets and to decreased and delayed striatal fast-firing interneuron activity. These effects of chronic stress on prefronto-striatal circuit dynamics could be blocked, or be mimicked, by selective optogenetic manipulation of these circuits. We suggest that altered excitation-inhibition dynamics of striosome-based circuit function could be an underlying mechanism by which chronic stress contributes to disorders characterized by aberrant decision-making under conflict.

The lateral habenula (LHb) is critical for modulation of negative reinforcement, punishment and aversive responses. In light of the success of deep-brain-stimulation (DBS) in the treatment of neurological disorders, we explored the use of LHb DBS as a method of intervention in cocaine selfadministration, extinction, and reinstatement in rats. An electrode was implanted into the LHb and rats were trained to self-administer cocaine (21 days; 0.25-1 mg/kg) until they achieved at least three days of stable performance (as measured by daily recordings of active lever presses in selfadministration cages). Thereafter, rats received DBS in the presence or absence of cocaine. DBS reduced cocaine seeking behavior during both self-administration and extinction training. DBS also attenuated the rats' lever presses following cocaine reinstatement (5-20 mg/kg) in comparison to sham-operated rats. These results were also controlled by the assessment of physical performance as measured by water self-administration and an open field test, and by evaluation of depressive-like manifestations as measured by the swim and two-bottles-choice tests. In contrast, LHb lesioned rats demonstrated increased cocaine seeking behavior as demonstrated by a delayed extinction response. In the ventral tegmental area, cocaine self-administration elevated glutamatergic receptor subunits NR1 and GluR1 and scaffolding protein PSD95, but not GABA A β, protein levels. Following DBS treatment, levels of these subunits returned to control values. We postulate that the effect of both LHb modulation and LHb DBS on cocaine reinforcement may be via attenuation of the cocaineinduced increase in glutaminergic input to the VTA.