Adult hippocampal neurogenesis buffers stress responses and depressive behaviour.

Glucocorticoids are released in response to stressful experiences and serve many beneficial homeostatic functions. However, dysregulation of glucocorticoids is associated with cognitive impairments and depressive illness. In the hippocampus, a brain region densely populated with receptors for stress hormones, stress and glucocorticoids strongly inhibit adult neurogenesis. Decreased neurogenesis has been implicated in the pathogenesis of anxiety and depression, but direct evidence for this role is lacking. Here we show that adult-born hippocampal neurons are required for normal expression of the endocrine and behavioural components of the stress response. Using either transgenic or radiation methods to inhibit adult neurogenesis specifically, we find that glucocorticoid levels are slower to recover after moderate stress and are less suppressed by dexamethasone in neurogenesis-deficient mice than intact mice, consistent with a role for the hippocampus in regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Relative to controls, neurogenesis-deficient mice also showed increased food avoidance in a novel environment after acute stress, increased behavioural despair in the forced swim test, and decreased sucrose preference, a measure of anhedonia. These findings identify a small subset of neurons within the dentate gyrus that are critical for hippocampal negative control of the HPA axis and support a direct role for adult neurogenesis in depressive illness.

Adult neurogenesis is necessary to refine and maintain circuit specificity.

The circuitry of the olfactory bulb contains a precise anatomical map that links isofunctional regions within each olfactory bulb. This intrabulbar map forms perinatally and undergoes activity-dependent refinement during the first postnatal weeks. Although this map retains its plasticity throughout adulthood, its organization is remarkably stable despite the addition of millions of new neurons to this circuit. Here we show that the continuous supply of new neuroblasts from the subventricular zone is necessary for both the restoration and maintenance of this precise central circuit. Using pharmacogenetic methods to conditionally ablate adult neurogenesis in transgenic mice, we find that the influx of neuroblasts is required for recovery of intrabulbar map precision after disruption due to sensory block. We further demonstrate that eliminating adult-born interneurons in naive animals leads to an expansion of tufted cell axons that is identical to the changes caused by sensory block, thus revealing an essential role for new neurons in circuit maintenance under baseline conditions. These findings show, for the first time, that inhibiting adult neurogenesis alters the circuitry of projection neurons in brain regions that receive new interneurons and points to a critical role for adult-born neurons in stabilizing a brain circuit that exhibits high levels of plasticity.

Modulation of BMAL/CLOCK/E-Box complex activity by a CT-rich cis-acting element.

The interaction between the BMAL1/CLOCK transcription factor and the cis-acting element known as the E-Box is a key event in the regulation of clock and clock-controlled gene expression. However, the fact that the ubiquitous E-Box element sits at the center of a presumably highly discriminating control system generates a certain level of puzzlement. Widely spread E-Boxes with a generic sequence CANNTG have been associated with expression of genes involved in a host of disparate biological processes, including the orchestration of circadian physiology. The intriguing specificity of this short DNA consensus element begs the hypothesis that its actual circadian properties might be encoded elsewhere, e.g., other factors or adjacent sequences. In a previous study, we found evidence that a short sequence in the mouse arginine vasopressin (AVP) proximal promoter has the ability to confer robust BMAL1/CLOCK responsiveness onto an adjacent E-Box. Here, we report the systematic analysis of this element. Our findings further define the determining features and sequence boundaries of this element, establish the effect of the photoperiod upon its interacting protein(s), and suggest that its cognate binding activity might be modulated by Zn2+ in a peripheral oscillator.

SREBP-1 as a transcriptional integrator of circadian and nutritional cues in the liver.

The act of feeding in mammals can generate such powerful cues for peripheral organs that, under certain conditions, they can override the entraining signals coming from the clock in the brain. Restricting the feeding time to the inactivity period, for example, can completely and quickly reverse the rhythms of gene expression in the liver. This manipulation does not affect the central oscillator in the suprachiasmatic nucleus, which is phase-locked to the light-dark cycle, but does release the peripheral oscillations in the liver from central control. It seems reasonable to predict the existence of one or more immediate response systems designed to sense the need to acutely reverse the sequence of absorptive and postabsorptive phases in the liver. In this study, the authors monitored the posttranslational activation of the sterol response element binding proteins from a circadian point of view to evaluate the role they might play in the circadian organization of the liver transcriptome as well as in the reversal of hepatic physiology that accompanies diurnal restricted feeding. This study highlights a possible direct link between the immediate effects of food consumption on the level of key membrane and humoral factors and the expression status of a set of coordinately regulated target genes in the liver.

A Transgenic Rat for Specifically Inhibiting Adult Neurogenesis.

The growth of research on adult neurogenesis and the development of new models and tools have greatly advanced our understanding of the function of newborn neurons in recent years. However, there are still significant limitations in the ability to identify the functions of adult neurogenesis in available models. Here we report a transgenic rat (TK rat) that expresses herpes simplex virus thymidine kinase in GFAP+ cells. Upon treating TK rats with the antiviral drug valganciclovir, granule cell neurogenesis can be completely inhibited in adulthood, in both the hippocampus and olfactory bulb. Interestingly, neurogenesis in the glomerular and external plexiform layers of the olfactory bulb was only partially inhibited, suggesting that some adult-born neurons in these regions derive from a distinct precursor population that does not express GFAP. Within the hippocampus, blockade of neurogenesis was rapid and nearly complete within 1 week of starting treatment. Preliminary behavioral analyses indicate that general anxiety levels and patterns of exploration are generally unaffected in neurogenesis-deficient rats. However, neurogenesis-deficient TK rats showed reduced sucrose preference, suggesting deficits in reward-related behaviors. We expect that TK rats will facilitate structural, physiological, and behavioral studies that complement those possible in existing models, broadly enhancing understanding of the function of adult neurogenesis.

Elovl3: a model gene to dissect homeostatic links between the circadian clock and nutritional status.

The ELOVL3 protein is a very long-chain fatty acid elongase found in liver, skin, and brown adipose tissues. Circadian expression of the Elovl3 gene in the liver is perturbed in mutant CLOCK mice but persists in mice with severe hepatic dysfunction. A reliance on an intact clock, combined with the refractoriness to liver decompensation and the finding of a robust sexually dimorphic pattern of expression, evince a particularly complex mode of transcriptional control. The Elovl3 gene upstream region was repressed by RevErbalpha and activated by sterol-regulatory element binding protein-1 (SREBP1) transcription factors. We propose that the temporal coordination of RevErbalpha and SREBP1 activities integrates clock and nutrition signals to drive a subset of oscillatory transcripts in the liver. Proteolytic activation of SREBP1 is circadian in the liver, and because the cycle of SREBP1 activation was reversed after restricting meals to the inactive phase of the day, this factor could serve as an acute sensor of nutritional state. SREBP1 regulates many known lipogenic and cholesterogenic circadian genes; hence, our results could explain how feeding can override brain-derived entraining signals in the liver. This mechanism would permit a rapid adjustment in the sequence of key aspects of the absorptive and postabsorptive phases in the liver.

A natural form of learning can increase and decrease the survival of new neurons in the dentate gyrus.

Granule cells born in the adult dentate gyrus undergo a 4-week developmental period characterized by high susceptibility to cell death. Two forms of hippocampus-dependent learning have been shown to rescue many of the new neurons during this critical period. Here, we show that a natural form of associative learning, social transmission of food preference (STFP), can either increase or decrease the survival of young granule cells in adult rats. Increased numbers of pyknotic as well as phospho-Akt-expressing BrdU-labeled cells were seen 1 day after STFP training, indicating that training rapidly induces both cell death and active suppression of cell death in different subsets. A single day of training for STFP increased the survival of 8-day-old BrdU-labeled cells when examined 1 week later. In contrast, 2 days of training decreased the survival of BrdU-labeled cells and the density of immature neurons, identified with crmp-4. This change from increased to decreased survival could not be accounted for by the ages of the cells. Instead, we propose that training may initially increase young granule cell survival, then, if continued, cause them to die. This complex regulation of cell death could potentially serve to maintain granule cells that are actively involved in memory consolidation, while rapidly using and discarding young granule cells whose training is complete to make space for new naïve neurons.

Circadian Transcription. Thinking outside the E-Box.

The E-Box is a widely used DNA control element. Despite its brevity and broad distribution the E-Box is a remarkably versatile sequence that affects many different genetic programs, including proliferation, differentiation, tissue-specific responses, and cell death. The circadian clock is one of the latest pathways shown to employ this element. In this context, E-Boxes are likely to play a key role in establishing the robust waves of gene expression characteristic of circadian transcription. The regulatory flexibility of the E-Box hinges on the sequence ambiguity allowed at its core, the strong influence of the surrounding sequences, and the recruitment of spatially and temporally regulated E-Box-binding factors. Therefore, understanding how a particular E-Box can accomplish a specific task entails the identification and systematic analysis of these cis- and trans-acting E-Box modifiers. In the present study we compared the E-Box-containing minimal promoters of vasopressin and cyclin B1, two genes that can respond to the transcriptional oscillators driving the circadian clock and cell cycle, respectively. Results of this comparison will help elucidate the manner in which discreet DNA modules associate to either augment or restrain the activation of potential circadian E-Boxes in response to competing regulatory signals.