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Background Neurological deficits of alcohol use disorder (AUD) have been attributed to dysfunctions of specific brain structures. Studies of alcoholic patients and chronic alcohol exposure animal models consistently identify reduced hippocampal mass and cogntive dysfunctions as a key alcohol-induced brain adaptation. However, the precise substrate of chronic alcohol exposure that leads to structural and functional impairments of the hippocampus is largely unknown. Methods Using a calorie-matched alcohol feeding method, we tested whether chronic alcohol exposure targets neural stem cells and neurogenesis in the adult hippocampus. The effect of alcohol on proliferation of neural stem cells as well as cell fate determination and survival of newborn cells was evaluated via BrdU pulse and chase methods. A retrovirus-mediated single-cell labeling method was used to determine the effect of alcohol on the morphological development and circuitry incorporation of individual hippocampal newborn neurons. Finally, Novel Object Recognition and Y-maze tests were performed to examine whether disrupted neurogenesis is associated with hippocampus-dependent functional deficits in alcohol-fed mice. Results Chronic alcohol exposure reduced proliferation of neural stem cells and survival rate of newborn neurons; however, the fate determination of newborn cells remained unaltered. Moreover, the dendritic spine density of newborn neurons significantly decreased in alcohol-fed mice. Impaired spine formation indicates that alcohol interfered the synaptic connectivity of newborn neurons with excitatory neurons originating from a various areas of the brain. In the Novel Object Recognition test, alcohol-fed mice displayed deficits in the ability to discriminate the novel object. Conclusions Our study revealed that chronic alcohol exposure disrupted multiple steps of neurogenesis, including the production and development of newborn neurons. In addition, chronic alcohol exposure altered connectivity of newborn neurons with other input neurons. Decreased neurogenesis and aberrant integration of newborn neurons into hippocampal networks are closely associated with deficits in hippocampus-dependent cognitive functions of alcohol-fed mice.

SummaryThe molecular mechanism of memory formation remains a mystery. Here, we show that TERT, the catalytic subunit of telomerase, gene knockout (Tert−/−) causes extremely poor ability in spatial memory formation. Knockdown of TERT in the dentate gyrus of adult hippocampus impairs spatial memory processes, while overexpression facilitates it. We find that TERT plays a critical role in neural development including dendritic development and neuritogenesis of hippocampal newborn neurons. A monosynaptic pseudotyped rabies virus retrograde tracing method shows that TERT is required for neural circuit integration of hippocampal newborn neurons. Interestingly, TERT regulated neural development and spatial memory formation in a reverse transcription activity-independent manner. Using X-ray irradiation, we find that hippocampal newborn neurons mediate the modulation of spatial memory processes by TERT. These observations reveal an important function of TERT through a non-canonical pathway and encourage the development of a TERT-based strategy to treat neurological disease-associated memory impairment.

Hippocampus-dependent cognitive and emotional function appears to be regionally dissociated along the dorsoventral (DV) axis of the hippocampus. Recent observations that adult hippocampal neurogenesis plays a critical role in both cognition and emotion raised an interesting question whether adult neurogenesis within specific subregions of the hippocampus contributes to these distinct functions. We examined the regional-specific and cell type-specific effects of fluoxetine, which requires adult hippocampal neurogenesis to function as an antidepressant, on the proliferation of hippocampal neural stem cells (NSCs). Fluoxetine specifically increased proliferation of NSCs located in the ventral region of the hippocampus while the mitotic index of NSCs in the dorsal portion of the hippocampus remained unaltered. Moreover, within the ventral hippocampus, type II NSC and neuroblast populations specifically responded to fluoxetine, showing increased proliferation; however, proliferation of type I NSCs was unchanged in response to fluoxetine. Activation or inhibition of serotonin receptor 1A (5-HTR1A) recapitulated or abolished the effect of fluoxetine on proliferation of type II NSCs and neuroblast populations in the ventral hippocampus. Our study showed that the effect of fluoxetine on proliferation is dependent upon the type and the position of the NSCs along the DV axis of the hippocampus.

The role of telomerase reverse transcriptase (TERT) has been extensively investigated in the contexts of aging and cancer. Interestingly, Tert−/− mice exhibit additional but unexpected aggressive and depressive behaviors, implying the potential involvement of TERT function in mood control. Our conditional rescue experiments revealed that the depressive and aggressive behaviors of Tert−/− mice originate from Tert deficiency in two distinct brain structures. Reactivation of Tert in the hippocampus was sufficient to normalize the depressive but not the aggressive behaviors of Tert−/− mice. Conversely, re-expression of Tert in the medial prefrontal cortex (mPFC) reversed the aggressive but not the depressive behavior of Tert−/− mice. Mechanistically, decreased serotonergic signaling and increased nitric oxide (NO) transmission in the hippocampus transduced Tert deficiency into depression as evidenced by our observation that the infusion of a pharmacological agonist for serotonin receptor 1a (5-HTR1A) and a selective antagonist for neuronal NO synthase into the hippocampus successfully normalized the depressive behavior of Tert−/− mice. In addition, increased serotonergic transmission by the 5-HTR1A agonist in the mPFC was sufficient to rescue the aggressive behavior of Tert−/− mice. Thus, our studies revealed a novel function of TERT in the pathology of depression and aggression in a brain structure-specific manner, providing direct evidence for the contribution of TERT to emotional control.