Adaptively responding to the environment is critical to optimal navigation of our world or “context”. The hippocampus plays a critical role in formation of episodic memories by encoding experiences or “contexts”. Processed sensory information is registered and decompressed to generate conjunctive representations which are then consolidated in hippocampal-prefrontal networks. Different hippocampal (DG-CA3-CA2-CA1) circuit mechanisms mediate memory discrimination (by reducing interference between similar memories), update previously consolidated representations and facilitate memory generalization (to support generation of schema for new learning and mediating predictable responses in changing contexts). Hippocampally computed mnemonic or contextual information gates recruitment of cortical and subcortical circuits to adaptively calibrate defensive and motivated behaviors (approach, avoidance, reward seeking etc.)
Contrary to over a hundred years of dogma that the adult mammalian brain does not regenerate, it is now recognized that the dentate gyrus (DG) sub region of the hippocampus is host to neurogenesis, the generation of functional neurons from neural stem cells, throughout life. This natural process of brain regeneration continuously remodels the DG-CA3 circuit through functional integration of adult-born neurons. Work by us and others has suggested that adult-born neurons play an important role in resolving interference and more recently, through population based coding mechanisms supporting pattern separation. Furthermore, adult hippocampal neurogenesis is exquisitely sensitive to environmental factors such as exercise, antidepressants, learning and stress including aging. Taken together, these observations suggest that adult hippocampal neurogenesis is an adaptive encoding mechanism by which neural stem cells generate new neurons commensurate with environmental demands on the hippocampal circuit to optimize hippocampal functions. One line of research in the lab investigates the regulation of neurogenesis in adulthood and aging.
It is intuitive to think how aberrations in hippocampal circuit mechanisms underlying memory processing or in linkage of mnemonic information with cortical and subcortical circuits are the basis for cognitive and mood impairments that characterize memory and psychiatric disorders. The mission of the Sahay lab is to generate insights to reverse these aberrations through investigation of molecular, circuit and network plasticity mechanisms supporting hippocampal memory processing and calibration of behavior in adulthood and aging. Towards this goal, we have undertaken a multifaceted bottom-up approach that integrates inducible mouse- and viral-genetics, pharmaco- and optogenetics, synaptic tracing, in vivo awake behaving optical imaging, ex vivo electrophysiology, in vivo electrophysiological recordings and behavioral analysis. Our projects are governed by the intuitive logic that elemental features of neural connectivity are prescribed by proteins, whose functions have been fine-tuned by evolution and experience. By identifying molecular determinants of elemental features of circuit wiring diagrams, we strive to ascribe causal relationships between circuit motifs and function. A major effort underway is aimed at how inhibitory neurons in intra- and extra hippocampal circuits are recruited to support memory (spatial and social) processing and route information to cortical and subcortical sites to calibrate motivated and defensive behaviors. Ultimately, we hope our efforts may guide strategies with broad therapeutic impact: to alleviate cognitive and mood impairments characterized by shared circuit substrates and hippocampal dysfunction (age-related cognitive decline, Autism spectrum disorders, Alzheimer’s disease and PTSD). Our ongoing efforts-discoveries and Intellectual Property- have already begun to illuminate potential therapeutic value of our 4R approach (Rejuvenation with new neurons, Re-engineering of inhibitory circuit connectivity, Restoration of hippocampal niche fitness and Replenishment of Cognitive Reserve) to improving memory in aging and MCI.
Click here Harvard BBS program Intro (August 2020)
1. How are neural stem cell activation-quiescence decisions physiologically regulated?
The decision to stay quiescent or generate a neuron is tightly regulated by environmental signals sensed directly by neural stem cells or niche components such as interneurons, endothelial cells and mature dentate granule neurons. Understanding the cell-autonomous and non-cell autonomous niche mechanisms by which the activation of neural stem cells and progenitors is regulated will inform how adult hippocampal neurogenesis functions as an adaptive encoding mechanism. We are probing the role of novel molecular factors in modulating neural stem cell activation-quiescence and symmetric/asymmetric division decisions and their regulation by specific stimuli such as stress. Targeting these factors may enable maintenance of the neural stem cell reservoir while stimulating adult hippocampal neurogenesis. Example: Vicidomini et al, Neuron 2020, Guo et al, Elife 2022, Vicidomini et al In progress.
2. What are the mechanisms underlying lineage homeostasis and experience dependent integration of adult-born neurons?
The functional integration of adult-born dentate granule neurons is tightly regulated so as to calibrate levels of neurogenesis commensurate with environmental demands. We are interested in how the activity and inputs onto mature dentate granule neurons influences neural stem cell activation and integration of young adult-born neurons into the circuit. By identifying the mechanisms underlying lineage homeostasis and neuronal competition, we may be able to leverage them to rejuvenate the dentate gyrus with stage-specific expansion of populations of adult-born neurons to enhance encoding and memory functions in adulthood, aging and in Alzheimer's disease. Example: McAvoy et al, Neuron 2016, Miller and Sahay, Nature Neuroscience 2019
3. How do properties and connectivity of dentate granule cells causally relate to their encoding and memory functions?
Elemental features of neural circuit wiring diagrams are prescribed by proteins whose functions have been fine-tuned by evolution and experience. By identifying and targeting such molecular prescriptions of connectivity within inhibitory microcircuits in DG-CA3/CA2, we may be able to enhance memory in aging, ASDs and MCI. We recently found that hippocampal parvalbumin inhibitory neurons dynamically regulate their output architecture in response to increased granule cell inputs and experience to support memory consolidation. This discovery has motivated us to investigate the molecular blueprint for how parvalbumin inhibitory neurons flexibly exert perisomatic inhibition onto principal neurons to regulate excitability, synchronize activity and promote network synchrony—properties critical to encoding, routing and storage of information.
Example: Guo et al, Nature Medicine 2018, Miller and Sahay, Nature Neuroscience 2019, Goode et al, Neuron 2020, Twarkowski et al, Elife 2022, Shih et al In Progress, Chung and Miller et al, in progress
4. How do DG-CA3 computations influence cortical and subcortical circuits subserving memory and mood?
Essential to understanding how adult hippocampal neurogenesis impacts memory processing, we need to interrogate how adult-born neurons influence neural activity in different hippocampal subregions. Although it is intuitive that hippocampus-based encoding of the environment dictates the way we respond to our environment, how encoding operations performed by adult-born neurons affect activity of prefrontal cortex, amygdala, hypothalamus to govern adaptive behavioral responses is poorly understood. A major focus of our efforts to address this question is investigating how inhibitory neurons in intra- and extra hippocampal circuits are recruited to support memory (spatial and social) processing and route information to cortical and subcortical sites to calibrate motivated and defensive behaviors. Example: Raam et al Nature Communications 2017, Besnard et al, Nature Neuroscience 2019, Goode, Tanaka et al, Neuron 2020, Besnard et al, Cell Reports 2020, Besnard and Sahay BBR 2020, Twarkowski et al, Elife 2022, Goode et al, in progress
5. Mechanisms underlying resilience and vulnerability to stress.
Most, if not all, psychiatric illnesses have their origins in the disruption of genetic and epigenetic programs that dictate embryonic and early-post natal development of neural circuits. We want to understand how alterations in neural circuits during the early postnatal period, when environment refines behaviors, and in adulthood contribute to perturbed affective behaviors and impairments in cognitive functions in adulthood. Importantly, we want to understand how the DG-CA3 circuit of the hippocampus modulate resilience and vulnerability to stress, a risk factor for many psychiatric disorders.
Example: Besnard et al, Cell Reports 2018