Abstract
While hippocampal hyperactivity is implicated in psychosis by both human and animal studies, whether it induces a hyperdopaminergic state and the underlying neural circuitry remains elusive. Previous studies established that region-specific inhibition of 14-3-3 proteins in the dorsal hippocampus CA1 (dCA1) induces schizophrenia-like behaviors in mice, including a novelty-induced locomotor hyperactivity. In this study, we showed that 14-3-3 dysfunction in the dCA1 over-activates ventral tegmental area (VTA) dopaminergic neurons, and such over-activation is necessary for eliciting psychomotor behavior in mice. We demonstrated that such hippocampal dysregulation of the VTA during psychomotor behavior is dependent on an over-activation of the lateral septum (LS), given that inhibition of the LS attenuates over-activation of dopaminergic neurons and psychomotor behavior induced by 14-3-3 inhibition in the dCA1. Moreover, 14-3-3 inhibition-induced neuronal activations within the dCA1-LS-VTA pathway and psychomotor behavior can be reproduced by direct chemogenetic activation of LS-projecting dCA1 neurons. Collectively, these results suggest that 14-3-3 dysfunction in the dCA1 results in hippocampal hyperactivation which leads to psychomotor behavior via a dCA1-LS-VTA pathway.
Highlights
The heterogeneity of psychiatric disorders poses major difficulties in deciphering their underlying etiology
We injected associated virus (AAV)-difopein or AAV-YFP into the dHP CA1 (dCA1) of wild type (WT) mice (Figure 2A) and examined the expression of c-Fos protein in the ventral tegmental area (VTA) following OFT. This protocol induced significantly increased numbers of total c-Fos-immunoreactive cells in the VTA of both difopein- and YFP-injected mice compared with their handled-only controls (Figures 2B,C), which is consistent with a previous report (Bourgeois et al, 2012) and suggests that the OFT induced neuronal activation in the VTA
We focused on identifying the neural circuitry mechanism underlying 14-3-3 dysfunction in the dCA1 induced psychosis-like behavior in mice
Summary
The heterogeneity of psychiatric disorders poses major difficulties in deciphering their underlying etiology. Consistent with this, studies using transgenic or developmental rodent models of schizophrenia associate a loss of hippocampal GABAergic interneurons activity (Belforte et al, 2010; Gilani et al, 2014) or increased hippocampal neuronal activity (higher firing rate, increased c-Fos, etc.) with psychomotor behavior (Lodge and Grace, 2007; Procaccini et al, 2011). Such behavioral abnormality can be rescued by restoring hippocampal GABAergic interneurons (Marissal et al, 2018) or by pharmacological or chemogenetic inhibition of hippocampal excitatory neurons (Maksimovic et al, 2014; Aitta-Aho et al, 2019). These findings support a hypothesis in which psychosis is a consequence of hippocampal excitation/inhibition (E/I) imbalance
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