Convergent inputs from the hippocampus and thalamus to the nucleus accumbens regulate dopamine neuron activity

Aberrant hippocampal activity is observed in individuals with schizophrenia and is thought to underlie the augmented dopamine system function associated with psychosis. The pathway by which the ventral hippocampus (vHipp) regulates dopamine neuron activity has been demonstrated previously and involves a glutamatergic projection to the nucleus accumbens (NAc). Recent post-mortem studies have confirmed glutamatergic abnormalities in the NAc of individuals with schizophrenia. Specifically, an increase in vesicular glutamate transporter 2 (vGlut2) expression was reported. While projections from the hippocampus do express vGlut2, inputs from the thalamus are more likely to account for this alteration; however, the role of thalamic inputs to the NAc in the regulation of dopamine neuron activity has not been elucidated. Here, using male Sprague Dawley rats, we demonstrate that a subset of NAc medium spiny neurons receive convergent inputs from the vHipp and paraventricular nucleus of the thalamus (PVT), with both regions working synergistically to regulate dopamine neuron activity. Activation of either the vHipp or PVT increases the number of spontaneously active dopamine neurons in the ventral tegmental area. Moreover, this regulation requires simultaneous activity in both regions, as PVT-inactivation can reverse vHipp-induced increases in dopamine neuron population activity, and vHipp-inactivation can reverse PVT-induced increases. This is relevant to schizophrenia as inactivation of either the vHipp or PVT is sufficient to reverse aberrant dopamine system function in two distinct rodent models. These data suggest that thalamic abnormalities may contribute to the aberrant dopamine system function observed in schizophrenia and that the PVT represents a novel site of intervention for psychosis. SIGNIFICANCE STATEMENT Current treatments for schizophrenia are far from adequate and a more complete understanding of the pathophysiology underlying this disease is warranted if we are to discover novel therapeutic targets. We have previously demonstrated that the aberrant dopamine system function, observed in individuals with schizophrenia and rodent models, is driven by increases in hippocampal activity. We now demonstrate that thalamic (paraventricular nucleus: PVT) and ventral hippocampal afferents converge in the nucleus accumbens to regulate dopamine system function. Such information provides a potential site for therapeutic intervention for schizophrenia. Indeed, inactivation of the PVT can effectively reverse aberrant dopamine system function in two distinct rodent models displaying circuit level alterations and corresponding behavioral deficits relevant to schizophrenia.