Material below summarizes the article Convergent Inputs from the Hippocampus and Thalamus to the Nucleus Accumbens Regulate Dopamine Neuron Activity, published on December 12, 2018, in JNeurosci and authored by Stephanie M. Perez and Daniel J. Lodge.
One of the main types of symptoms experienced by people with schizophrenia are positive symptoms, which include hallucinations, delusions, and paranoia. This psychosis is thought to be mediated by aberrant dopamine signaling, but the cause of this aberrant signaling has not been conclusively demonstrated.
We previously investigated the afferent regulation of the dopamine system and identified a glutamatergic pathway from the ventral hippocampus to the nucleus accumbens (NAc) crucial to the regulation of dopamine neurons in the ventral tegmental area (VTA). Given that individuals with schizophrenia exhibit hyperactivity in hippocampal subfields that is correlated with the severity of positive symptoms, it is likely the dopamine dysfunction in schizophrenia is driven by aberrant ventral hippocampal activity.
Consistent with this hypothesis, recent postmortem studies revealed glutamatergic abnormalities in the NAc, specifically in expression of vesicular glutamate transporter 2 (vGlut2). Because the hippocampus expresses vGlut2 at relatively low levels, we began to explore areas with high levels of vGlut2 expression such as the thalamus, a structure composed of many subnuclei that has previously been implicated in schizophrenia. Of importance to our work is the paraventricular nucleus of the thalamus (PVT), which has been shown to provide a dense glutamatergic projection to the NAc.
In our study, we used male Sprague-Dawley rats to examine the contribution of the PVT to the regulation of VTA dopamine neuron activity. We demonstrated a subpopulation of medium spiny neurons in the NAc received convergent inputs from both the ventral hippocampus and PVT. Electrophysiological studies suggested that these two regions work synergistically to regulate downstream activity of dopamine neurons. Activation of either the ventral hippocampus or PVT caused a significant increase in the population activity (average number of spontaneously active neurons) of VTA dopamine neurons, similar to what is observed in rodent models of schizophrenia. This regulation requires activity from both regions, as indicated by the fact that PVT inactivation can reverse ventral hippocampally induced increases, and that inactivation of the ventral hippocampus can reverse PVT-induced increases in population activity.
To investigate how this regulation is affected in schizophrenia, we used two models of the disease. A hallmark of these rodent models is a significant increase in the population activity of VTA dopamine neurons. This is important because this increase in dopamine activity correlates with psychosis observed in schizophrenia. Previous studies have shown pharmacological inactivation of the ventral hippocampus is sufficient to reverse increases in population activity. Likewise, we demonstrated inactivation of the PVT is also sufficient to restore normal dopamine system function in both rodent models.
Schizophrenia remains a debilitating psychotic disorder with no cure. Current antipsychotic therapies for the treatment of schizophrenia are inadequate, as they are ineffective at treating all symptoms associated with the disease. Additionally, patients often discontinue treatment due to the severe side-effects associated with the drugs. Alternate therapies are needed to better treat individuals with schizophrenia, and a more complete understanding of the systems contributing to pathophysiology is required to discover novel therapeutic targets. The data collected from this study suggest thalamic abnormalities may also contribute to the aberrant dopamine system function present in schizophrenia and thus provide a potential site for therapeutic intervention for schizophrenia.
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Convergent Inputs from the Hippocampus and Thalamus to the Nucleus Accumbens Regulate Dopamine Neuron Activity. Stephanie M. Perez and Daniel J. Lodge. JNeurosci 12 Dec 2018, 38 (50) 10607–10618; DOI: 10.1523/JNEUROSCI.2629-16.2018