Post by Elisa Guma

What's the science?

Abnormal hippocampal activity is often observed in individuals with schizophrenia and has been associated with increased dopamine signalling, a hallmark of schizophrenia. Increased dopamine signalling is thought to contribute to the positive symptoms of schizophrenia (i.e. delusions and hallucinations). However, abnormal dopamine regulation could actually be a result of aberrant glutamate activity; specifically, glutamatergic projections from the ventral hippocampus to the nucleus accumbens have been shown to regulate dopamine in the ventral tegmental area (a dopamine rich region). Recent research has identified increased expression of vesicular glutamate transporter 2 in schizophrenic patients — a transporter required for glutamate uptake into synaptic vesicles. Interestingly, projections from the paraventricular nucleus of the thalamus (PVT) to the nucleus accumbens have been shown to highly express this transporter. However, it is still unclear if these thalamic inputs to the nucleus accumbens regulate dopamine neuron activity alongside ventral hippocampal inputs. This week in the Journal of Neuroscience, Perez and Lodge performed a series of experiments using in vivo electrophysiology and chemogenetics to demonstrate that projections from the PVT and ventral hippocampus converge in the nucleus accumbens to regulate dopamine neuron activity in the ventral tegmental area.

How did they do it?

In male rats, the authors used in vivo electrophysiology to investigate how activation or inactivation of the PVT or ventral hippocampus (via intracerebral infusion of tetrodotoxin citrate, NMDA, kynurenic acid, or vehicle) would affect dopamine neuron activity of the ventral tegmental area. They then used Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-based chemogenetic tools to study the same circuitry. Briefly, DREADD involves chemically engineered receptors that respond to exogenous chemicals (in this case clozapine-N-oxide) to affect the activity of cells in which these designer receptors are expressed. The authors injected DREADDs into the PVT or ventral hippocampus, and then used clozapine-N-oxide to activate the DREADDs in the nucleus accumbens. Again, they recorded dopamine neuron activity in the ventral tegmental area (where dopamine is released) in response to these manipulations.

In a separate experiment, the authors used a retrograde virus to express DREADDs either along the projections from the PVT to the nucleus accumbens, or from the ventral hippocampus to nucleus accumbens. They activated these pathways by administering a DREADD activator systemically instead of through intracerebral infusion, and then recorded dopamine neuron activity. Finally, they used two common animal models of schizophrenia, induced by prenatal exposure to neurotoxins. Again, they recorded dopamine activity in the ventral tegmental area in response to pharmacological inactivation of the PVT and ventral hippocampus.

What did they find?

The authors showed that activation of the PVT (with NMDA infusion) increased dopamine neuron activity and that this was reversed by blocking ventral hippocampal activity (with TTX). This demonstrated that the PVT depends on the ventral hippocampus to increase ventral tegmental area dopamine neuron activity. Next, they found that the increase in dopamine activity due to PVT activation (with NMDA infusion) was not reversed by blocking ventral hippocampal glutamate activity specifically. Instead, they showed that inhibiting glutamate transmission in the nucleus accumbens decreased PVT induced dopamine increases in the ventral tegmental area. This suggests that the increase in dopamine activity observed were due to activation of glutamatergic projections to the nucleus accumbens, and not the ventral hippocampus. The authors’ chemogenetic experiments showed that activation of the pathway from the PVT to the nucleus accumbens caused a significant increase in dopamine neuron activity of the ventral tegmental area. As a control for the specificity of their findings, they showed that activation of projections from the PVT to the medial prefrontal cortex had no effects on dopamine activity.