Amar Sahay's research while affiliated with Massachusetts General Hospital and other places
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Publications (55)
Heterozygous mutations in the Dual specificity tyrosine-phosphorylation-regulated kinase 1a Dyrk1a gene define a syndromic form of Autism Spectrum Disorder. The synaptic and circuit mechanisms mediating Dyrk1a functions in social cognition are unclear. Here, we identify a social experience-sensitive mechanism in hippocampal mossy fiber-parvalbumin...
Memories encoded in the dentate gyrus (DG) - CA3 circuit of the hippocampus are routed from CA1 to anterior cingulate cortex (ACC) for consolidation. Although CA1 parvalbumin inhibitory neurons (PV INs) orchestrate hippocampal-cortical communication, we know less about CA3 PV INs or DG - CA3 principal neuron - IN circuit mechanisms that contribute...
Experience governs neurogenesis from radial-glial neural stem cells (RGLs) in the adult hippocampus to support memory. Transcription factors in RGLs integrate physiological signals to dictate self-renewal division mode. Whereas asymmetric RGL divisions drive neurogenesis during favorable conditions, symmetric divisions prevent premature neurogenesi...
Experience governs neurogenesis from radial-glial neural stem cells (RGLs) in the adult hippocampus to support memory. Transcription factors in RGLs integrate physiological signals to dictate self-renewal division mode. Whereas asymmetric RGL divisions drive neurogenesis during favorable conditions, symmetric divisions prevent premature neurogenesi...
Memories encoded in the dentate gyrus (DG)-CA3 circuit of the hippocampus are routed from CA1 to anterior cingulate cortex (ACC) for consolidation. Although CA1 parvalbumin inhibitory neurons (PV INs) orchestrate hippocampal-cortical communication, we know less about CA3 PV INs or DG-CA3 principal neuron-IN circuit mechanisms that contribute to evo...
Chronic, sustained exposure to stressors can profoundly affect tissue homeostasis, although the mechanisms by which these changes occur are largely unknown. Here we report that the stress hormone corticosterone—which is derived from the adrenal gland and is the rodent equivalent of cortisol in humans—regulates hair follicle stem cell (HFSC) quiesce...
Hippocampal circuitry is continuously modified by integration of adult-born dentate granule cells (DGCs). Prior work has shown that enhancing adult hippocampal neurogenesis decreases interference or overlap or conflict between ensembles of similar contexts and promotes discrimination of a shock-associated context from a similar, neutral context. Ho...
Glandular epithelia, including the mammary and prostate glands, are composed of basal cells (BCs) and luminal cells (LCs)1,2. Many glandular epithelia develop from multipotent basal stem cells (BSCs) that are replaced in adult life by distinct pools of unipotent stem cells1,3–8. However, adult unipotent BSCs can reactivate multipotency under regene...
The hippocampus and its extended network contribute to encoding and recall of episodic experiences. Drawing from recent anatomical, physiological, and behavioral studies, we propose that hippocampal engrams function as indices to mediate memory recall. We broaden this idea to discuss potential relationships between engrams and hippocampal place cel...
Considerable work emphasizes a role for hippocampal circuits in governing contextual fear discrimination. However, the intra- and extrahippocampal pathways that route contextual information to cortical and subcortical circuits to guide adaptive behavioral responses are poorly understood. Using terminal-specific optogenetic silencing in a contextual...
Radial glia-like neural stem cells (RGLs) in the dentate gyrus subregion of the hippocampus give rise to dentate granule cells (DGCs) and astrocytes throughout life, a process referred to as adult hippocampal neurogenesis. Adult hippocampal neurogenesis is sensitive to experiences, suggesting that it may represent an adaptive mechanism by which hip...
The dentate gyrus–CA3 circuit of the hippocampus is continuously modified by the integration of adult-born dentate granule cells (abDGCs). All abDGCs undergo a prolonged period of maturation, during which they exhibit heightened synaptic plasticity and refinement of electrophysiological properties and connectivity. Consistent with theoretical model...
Novel approaches to address cognitive aging and to delay or prevent cognitive decline in older individuals will require a better understanding of the biological and environmental factors that contribute to it. Studies in animal models-in particular, animals whose cognitive trajectory across their life span closely tracks that of humans-can provide...
Adaptive fear responses to external threats rely upon efficient relay of computations underlying contextual encoding to subcortical circuits. Brain-wide analysis of highly coactivated ensembles following contextual fear discrimination identified the dorsolateral septum (DLS) as a relay of the dentate gyrus–CA3 circuit. Retrograde monosynaptic traci...
Stress exposure is associated with the pathogenesis of psychiatric disorders, including post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). Here, we show in rodents that chronic stress exposure rapidly and transiently elevates hippocampal expression of Kruppel-like factor 9 (Klf9). Inducible genetic silencing of Klf9 expressi...
Citation for this corrigendum: J Clin Invest. 2018;128(6):2651. https://doi.org/10.1172/JCI121592. During the assembly of Figure 4A, an incorrect image was inadvertently used for the SVZ section for the whole-body XRT sample. The correct figure panel is below. (Figure presented).
Memories become less precise and generalized over time as memory traces reorganize in hippocampal–cortical networks. Increased time-dependent loss of memory precision is characterized by an overgeneralization of fear in individuals with post-traumatic stress disorder (PTSD) or age-related cognitive impairments. In the hippocampal dentate gyrus (DG)...
The original version of this Article contained an error in the spelling of the author Alexa H. Veenema, which was incorrectly given as Alexa Veenema. This has now been corrected in both the PDF and HTML versions of the Article.
Oxytocin receptor (Oxtr) signaling in neural circuits mediating discrimination of social stimuli and affiliation or avoidance behavior is thought to guide social recognition. Remarkably, the physiological functions of Oxtrs in the hippocampus are not known. Here we demonstrate using genetic and pharmacological approaches that Oxtrs in the anterior...
Nervous system injury is a frequent result of cancer therapy involving cranial irradiation, leaving patients with marked memory and other neurobehavioral disabilities. Here, we report an unanticipated link between bone marrow and brain in the setting of radiation injury. Specifically, we demonstrate that bone marrow-derived monocytes and macrophage...
Neural stem cells (NSCs) within the hippocampal niche integrate local cues, such as activity of inhibitory interneurons, into their homeostatic fate choices. Now in Cell Stem Cell, Bao et al. (2017) describe how these local interneurons relay signals from distal brain regions to govern NSC quiescence and activation. Neural stem cells (NSCs) within...
Major depression is hypothesized to be associated with dysregulations of the hypothalamic-pituitary-adrenal (HPA) axis and impairments in adult hippocampal neurogenesis. Adult-born hippocampal neurons are required for several effects of antidepressants and increasing the rate of adult hippocampal neurogenesis (AHN) before exposure to chronic cortic...
Millions of individuals suffer from age-related cognitive decline, defined by impaired memory precision. Increased understanding of hippocampal circuit mechanisms underlying memory formation suggests a role for computational processes such as pattern separation and pattern completion in memory precision. We describe evidence implicating the dentate...
Graphical Abstract Highlights d SIRT6 loss causes pathological changes in behavior, DNA damage, apoptosis, and Tau d Tau is stabilized and hyperphosphorylated by GSK3 in the absence of SIRT6 d Phenotypes in SIRT6 knockout cells can be rescued by GSK3 or ATM inhibition d Patients with Alzheimer's disease show a severe decrease in SIRT6 levels In Bri...
The neural circuit mechanisms underlying the integration and functions of adult-born dentate granule cell (DGCs) are poorly understood. Adult-born DGCs are thought to compete with mature DGCs for inputs to integrate. Transient genetic overexpression of a negative regulator of dendritic spines, Kruppel-like factor 9 (Klf9), in mature DGCs enhanced i...
Neuropsychopharmacology, the official publication of the American College of Neuropsychopharmacology, publishing the highest quality original research and advancing our understanding of the brain and behavior.
There is growing recognition that the dentate gyrus (DG) subregion of the hippocampus contributes to both cognition and regulation of mood. Because adult hippocampal neurogenesis provides a source of new neurons throughout life in mammals, it represents a unique form of neural plasticity that may be targeted to restore or rejuvenate DG functions wh...
The dentate gyrus (DG) of mammals harbors neural stem cells that generate new dentate granule cells (DGCs) throughout life. Behavioral studies using the contextual fear discrimination paradigm have found that selectively augmenting or blocking adult hippocampal neurogenesis enhances or impairs discrimination under conditions of high, but not low, i...
Over the past several decades, the proliferation and integration of adult-born neurons into existing hippocampal circuitry has been implicated in a wide range of behaviors, including novelty recognition, pattern separation, spatial learning, anxiety behaviors, and antidepressant response. In this review, we suggest that the diversity in behavioral...
The generalization of fear is an adaptive, behavioral and physiological response to the likelihood of threat in the environment. In contrast, the overgeneralization of fear, a cardinal feature of post-traumatic stress disorder (PTSD), manifests as inappropriate, uncontrollable expression of fear in neutral and safe environments. Overgeneralization...
Fluoxetine, a selective serotonin-reuptake inhibitor (SSRI), is known to induce structural rearrangements and changes in synaptic transmission in hippocampal circuitry. In the adult hippocampus, structural changes include neurogenesis, dendritic and axonal plasticity of pyramidal and dentate granule neurons, and dedifferentiation of dentate granule...
Adult hippocampal neurogenesis is increased by antidepressants, and is required for some of their behavioral effects. However, it remains unclear whether expanding the population of adult-born neurons is sufficient to affect anxiety and depression-related behavior. Here, we use an inducible transgenic mouse model in which the pro-apoptotic gene Bax...
Adult-born dentate granule neurons contribute to memory encoding functions of the dentate gyrus (DG) such as pattern separation. However, local circuit-mechanisms by which adult-born neurons partake in this process are poorly understood. Computational, neuroanatomical and electrophysiological studies suggest that sparseness of activation in the gra...
New neurons are produced within the hippocampus of the mammalian brain throughout life. Evidence from animal studies has suggested that the function of these adult-born neurons is linked to cognition and emotion. Until we are able to detect and measure levels of adult neurogenesis in living human brains-a formidable challenge for now-we cannot esta...
W104. Adult Hippocampal Neurogenesis Modulates Excitability of the Dentate Gyrus
Amar Sahay*, Taruna Ikrar, Sally Levinson, Antoine Besnard, Alexis Hill, Rene Hen, Xiangmin Xu
MGH, Harvard Stem Cell Institute and Harvard Medical School, Boston, Massachusetts
Background: Adult hippocampal neurogenesis is a unique form of plasticity that generates...
Although an influence of adult neurogenesis in mediating some of the effects of antidepressants has received considerable attention in recent years, much less is known about how alterations in this form of plasticity may contribute to psychiatric disorders such as anxiety and depression. One way to begin to address this question is to link the func...
While adult-born neurons in the olfactory bulb (OB) and the dentate gyrus (DG) subregion of the hippocampus have fundamentally different properties, they may have more in common than meets the eye. Here, we propose that new granule cells in the OB and DG may function as modulators of principal neurons to influence pattern separation and that adult...
Adult hippocampal neurogenesis is a unique form of neural circuit plasticity that results in the generation of new neurons in the dentate gyrus throughout life. Neurons that arise in adults (adult-born neurons) show heightened synaptic plasticity during their maturation and can account for up to ten per cent of the entire granule cell population. M...
In the adult mammalian brain, neurogenesis originates from astrocyte-like stem cells. We generated a transgenic mouse line in which the tetracycline dependent transactivator (tTA) is expressed under the control of the murine GFAP promoter. In this mouse line, inducible gene expression targets virtually all GFAP-expressing stem-like cells in the den...
The dentate gyrus (DG) is modified throughout life by integration of new adult-born neurons. Similarities in neuronal maturation during DG development and adult hippocampal neurogenesis suggest that genetically encoded intrinsic regulatory mechanisms underlying these temporally distinct processes are conserved and reused. Here, we identify a novel...
Various chronic antidepressant treatments increase adult hippocampal neurogenesis, but the functional importance of this phenomenon remains unclear. Using radiological and genetic methods, we show that disrupting neurogenesis blocks behavioural responses to antidepressants. X-irradiation of a restricted region of mouse brain containing the hippocam...
The development of new treatments for depression is predicated upon identification of neural substrates and mechanisms that underlie its etiology and pathophysiology. The heterogeneity of depression indicates that its origin may lie in dysfunction of multiple brain regions. Here we evaluate adult hippocampal neurogenesis as a candidate mechanism fo...
Major depressive disorder (MDD) is a debilitating and complex psychiatric disorder that involves multiple neural circuits and genetic and non-genetic risk factors. In the quest for elucidating the neurobiological basis of MDD, hippocampal neurogenesis has emerged as a candidate substrate, both for the etiology as well as treatment of MDD. This chap...
Citations
... The anterior cingulate cortex (ACC) to amygdala circuit is 43 essential for acquisition of observational CFC memory 16 . A subset of ACC neurons in the observer 44 respond to aversive events occurring in the demonstrator, which delivers an unconditioned 45 stimulus (US) to the amygdala and the US signal is associated with the context as a conditioned 1 stimulus (CS) to form observational CFC memory in the amygdala 5,16,18 . 2 However, several outstanding questions regarding both behavioral and neurobiological 3 aspects of observational CFC memory remain unexplored. First, how long does observational CFC 4 memory persist in the observer? ...
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... Researchers have identified that Kruppel-like factor 9 (Klf9), a key transcription factor for the stemness of NSCs, is elevated in qNSCs and functions as a brake on symmetric self-renewal in the adult hippocampus. Inducible deletion of Klf9 promotes the activation of qNSCs [59]. Notch signaling is known to play a vital role in maintaining the quiescence of NSCs in the adult mouse SVZ. ...
... Yin et al. found a micromolecular hexasaccharide OG6, which was able to promote regulatory T cells mobilization around HFs and stimulate the regeneration of robust hairs [133]. Psychological stress can lead to the increasing production of stress hormones (glucocorticoids) that cause defective activation of hair follicle stem cells, leading to hair loss [134]. These studies provide new ideas for hair regeneration through biomaterials. ...
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... The hippocampal schematic matching model of fear generalization is supported by cross-species findings. Rodent hippocampal facilitation and disruption (particularly of the dentate gyrus subregion) has been shown to strengthen (9,10) and weaken (11,12) fear discrimination (the inverse of generalization), respectively. In human neuroimaging studies, hippocampal activations have been shown to increase as stimuli Published by Elsevier Inc on behalf of Society of Biological Psychiatry. ...
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... Lineage plasticity is defined by the dual expression of cell identity transcription factors of both new and prior lineages and is typical of wound-induced stress pathways that bestow stem cells with fate flexibility (4). This state has been observed across multiple tissues in regeneration-inducing settings, including wounding, neighboring cell death, and transplantation (5)(6)(7)(8)(9). In healthy tissues, stem cells ultimately either return to their prior niche-defined trajectory or undergo a fate change upon entering a different microenvironment. ...
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... We have elucidated the functional dynamics of the hippocampus, emphasizing the crucial role of sequential activation from the mPP to DG and from the SC to the CA regions. This supports the concept of the hippocampus as a dynamic indexer, intricately linking detailed memories across the cortex through well-coordinated cell assemblies 55 . Our observations on how various phases of network-LTP are vital for memory encoding in specific layers highlight the potential of EVOX to propel our comprehension of complex neural mechanisms. ...
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... Although GLP-1R is widely expressed in brain, the physiological role of GLP-1R neurons in mediating food intake and body weight remains elusive. One brain region that strongly expresses GLP-1R is the dorsolateral septum (dLS) [13; 14], a subcortical forebrain area that exerts influences over feeding behavior [15][16][17][18], sleep [19], learning and memory [20][21][22], mood and motivation [23; 24]. Previous studies have suggested GLP-1 acts in the lateral septum to control feeding. ...
... Under physiological conditions, native NSCs in the adult mouse DG generate new neurons and astrocytes, which integrate into the hippocampus' complex cellular architecture and functional circuits, and contribute to hippocampal-dependent learning, memory and mood regulation 14,35,55,56 . Here, we aimed to understand how TBI affects specific populations of NSC-derived cells in the DG. ...
... Early postnatal life, which primarily involves neurogenesis, neuritogenesis, synaptogenesis, and synaptic pruning, is crucial for neuronal development (Bond et al. 2015;Denoth-Lippuner and Jessberger 2021;Kempermann et al. 2018;Sorrells et al. 2018). Neurogenesis in the early postnatal period is vigorous and newborn neurons will integrate into circuits that are critical for learning and cognition in the hippocampus (Miller and Sahay 2019;Salta et al. 2023). Microglia are natural resident immune cells in the brain and play a major role in eliminating dying neurons, pruning synapses, and releasing trophic substances to support neuronal survival (Badimon et al. 2020). ...
... Given the absence of a cure, it is important to identify and study factors that contribute to cognitive resilience in healthy older individuals and people with dementia (Austad et al., 2019). Indeed, engagement in certain activities and lifestyle choices has been shown to lead to more successful CA outcomes (Harada et al., 2013). ...
