Reversing neural circuit and behavior deficit in mice exposed to maternal inflammation by Zika virus.
Publication Year:
2021
PubMed ID:
34232545
Funding Grants:
Public Summary:
This study investigates the impact of Zika virus (ZIKV) infection during pregnancy on the behavior and brain development of offspring in a mouse model. The researchers found that ZIKV infection led to immune activation in pregnant mice and resulted in offspring displaying behaviors similar to autism, such as repetitive self-grooming and impaired social memory. In the medial prefrontal cortex (mPFC) of affected offspring, there was an imbalance between excitation and inhibition, along with increased brain activity. This imbalance was linked to the disruption of inhibitory neurons and synapses and heightened neural activity from the ventral hippocampus (vHIP) projecting to the mPFC. The researchers also observed structural changes in synaptic connections and the way vHIP neurons connect to mPFC neurons, leading to an overactive vHIP-mPFC pathway. Interestingly, when they reduced the activity of vHIP neurons projecting to the mPFC using a specific method, it improved social memory in the affected offspring. In summary, this study reveals that Zika virus infection during pregnancy can cause maternal immune activation and result in autism-like behaviors in offspring, associated with changes in brain connectivity between the ventral hippocampus and the prefrontal cortex. Understanding these mechanisms could have implications for future research into neurodevelopmental disorders and potential interventions.
Scientific Abstract:
Zika virus (ZIKV) infection during pregnancy is linked to various developmental brain disorders. Infants who are asymptomatic at birth might have postnatal neurocognitive complications. However, animal models recapitulating these neurocognitive phenotypes are lacking, and the circuit mechanism underlying behavioral abnormalities is unknown. Here, we show that ZIKV infection during mouse pregnancy induces maternal immune activation (MIA) and leads to autistic-like behaviors including repetitive self-grooming and impaired social memory in offspring. In the medial prefrontal cortex (mPFC), ZIKV-affected offspring mice exhibit excitation and inhibition imbalance and increased cortical activity. This could be explained by dysregulation of inhibitory neurons and synapses, and elevated neural activity input from mPFC-projecting ventral hippocampus (vHIP) neurons. We find structure alterations in the synaptic connections and pattern of vHIP innervation of mPFC neurons, leading to hyperconnectivity of the vHIP-mPFC pathway. Decreasing the activity of mPFC-projecting vHIP neurons with a chemogenetic strategy rescues social memory deficits in ZIKV offspring mice. Our studies reveal a hyperconnectivity of vHIP to mPFC projection driving social memory deficits in mice exposed to maternal inflammation by ZIKV.