CIRCUIT-SPECIFIC ACTIVATION OF THE DORSAL CA1 - MPFC PATHWAY AS A MECHANISM FOR DOPAMINE DYSREGULATION IN SCHIZOPHRENIA RELEVANT BEHAVIORS

Dysregulation of hippocampal-prefrontal-midbrain circuitry has been proposed as a core mechanism underlying disruption of striatal dopamine release. In particular, hyperactivity of the dorsal CA1 (dCA1) and its glutamatergic projections to the prelimbic medial prefrontal cortex (PL-mPFC) may alter prefrontal regulation of ventral tegmental area (VTA) dopamine neuron activity. However, the contribution of this projection to dopamine-dependent behavior has remained unresolved.
In this study, we examined whether selective activation of the dCA1-PL pathway was sufficient to modulate dopamine-related behavioral phenotypes. We used a projection-specific chemogenetic approach in adult C57BL/6J mice, injecting AAVretro-Cre into the PL-mPFC and a Cre-dependent excitatory DREADD (hM3Dq) or control vector into dCA1, thus confining receptor expression to dCA1 neurons that project to the mPFC. Pathway activation was induced by systemic administration of clozapine-N-oxide (CNO; 1 mg/kg). Dopamine-dependent behavior was evaluated using open-field locomotion under baseline conditions and following amphetamine administration, as well as an overshadowing paradigm to evaluate salience attribution, previously linked with striatal dopamine function. Whole-cell patch-clamp recordings from fluorescently identified dCA1 pyramidal neurons were performed, to verify pathway-selective increases in intrinsic excitability following CNO application.
Selective activation of the dCA1-PL projection produced significant upregulation of PL pyramidal neuron activity, as well as reductions in amphetamine-induced locomotion, indicating that dorsal hippocampal output to mPFC is sufficient to modify dopamine-sensitive behavioral processes. Together, these findings link hippocampal circuit dysfunction to dopaminergic abnormalities, which play a role in schizophrenia psychopathology as well as other neuropsychiatric illnesses.