Motivation for reward drives adaptive behaviors, whereas impairment of reward perception and experience (anhedonia) can contribute to psychiatric diseases, including depression and schizophrenia. We sought to test the hypothesis that the medial prefrontal cortex (mPFC) controls interactions among specific subcortical regions that govern hedonic responses. By using optogenetic functional magnetic resonance imaging to locally manipulate but globally visualize neural activity in rats, we found that dopamine neuron stimulation drives striatal activity, whereas locally increased mPFC excitability reduces this striatal response and inhibits the behavioral drive for dopaminergic stimulation. This chronic mPFC overactivity also stably suppresses natural reward-motivated behaviors and induces specific new brainwide functional interactions, which predict the degree of anhedonia in individuals. These findings describe a mechanism by which mPFC modulates expression of reward-seeking behavior, by regulating the dynamical interactions between specific distant subcortical regions.

Tourette syndrome (TS) is a childhood neuropsychiatric disorder characterized by motor and vocal tics. Imaging studies found alterations in caudate (Cd) and putamen volumes. To investigate possible alterations in cell populations, postmortem basal ganglia tissue from individuals with TS and normal controls was analyzed by using unbiased stereological techniques. A markedly higher total neuron number was found in the globus pallidus pars interna (GPi) of TS. In contrast, a lower neuron number and density was observed in the globus pallidus pars externa and in the Cd. An increased number and proportion of the GPi neurons were positive for the calcium-binding protein parvalbumin in tissue from TS subjects, whereas lower densities of parvalbumin-positive interneurons were observed in both the Cd and putamen of TS subjects. This change is consistent with a developmental defect in tangential migration of some GABAergic neurons. The imbalance in striatal and GPi inhibitory neuron distribution suggests that the functional dynamics of cortico-striato-thalamic circuitry are fundamentally altered in severe, persistent TS.T ourette syndrome (TS) is a childhood neuropsychiatric disorder characterized by persistent motor and vocal tics, which may or may not abate upon entering adulthood. Tics are sudden stereotyped motor sequences of varying intensity and complexity, often preceded by compulsions or sensory phenomena. Neither the etiology nor the pathophysiology of TS is well understood. Both genetic and environmental factors are thought to be important, but the exact role of each has not yet been identified (1). Epigenetic events that increase the risk of developing tic disorder or TS include perinatal hypoxic-ischemic events that damage the periventricular germinal matrix and adjacent deep regions of the brain (2). A considerable amount of data implicates the cortico-striato-thalamo-cortical circuit in TS pathophysiology, particularly basal ganglia (BG) abnormalities. The BG, a richly interconnected set of nuclei, is essential for the initiation and correct implementation of learned sequences of motor and cognitive segments that characterize purposive behavior. The two major inputs into the BG, from the cerebral cortex and the intralaminar nuclei of the thalamus, enter into the striatum, which consists of the caudate (Cd) and putamen (Pt). The firing of cortical inputs drives activity in both medium spiny neurons (MSNs) (3) and several types of interneurons, including parvalbumin (PV)-positive (PVϩ) GABAergic interneurons (4). Striatal PVϩ interneurons are connected by electrical junctions and form a web of inhibitory synapses throughout the striatum, coordinating the activities of MSNs, and likely increasing their threshold of firing in response to cortical inputs (5, 6). MSNs, which are the large majority of neurons in the striatum, project to the globus pallidus pars interna (GPi), either directly or indirectly via the subthalamic nucleus and the globus pallidus pars externa (GPe). These two pathways can be differentiate...

Cortico-basal ganglia neuronal ensembles bring automatic motor skills into voluntary control and integrate them into ongoing motor behavior. A 5% decrease in caudate (Cd) nucleus volume is the most consistent structural finding in the brain of patients with Tourette syndrome (TS), but the cellular abnormalities that underlie this decrease in volume are unclear. In this paper, the density of different types of interneurons and medium spiny neurons (MSNs) in the striatum was assessed in the postmortem brains of 5 TS subjects as compared with normal controls (NC) by unbiased stereological analyses. TS patients demonstrated a 50-60% decrease of both parvalbumin (PV)+ and choline acetyltransferase (ChAT)+ cholinergic interneurons in the Cd and the putamen (Pt). Cholinergic interneurons were decreased in TS patients in the associative and sensorimotor regions but not in the limbic regions of the striatum, such that the normal gradient in density of cholinergic cells (highest in associative regions, intermediate in sensorimotor and lowest in limbic regions) was abolished. No significant difference was present in the densities of medium-sized calretinin (CR)+ interneurons, MSNs and total neurons. The selective deficit of PV+ and cholinergic striatal interneurons in TS subjects may result in an impaired cortico/thalamic control of striatal neuron firing in TS.