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 therapeutic strategies to alleviate cognitive and mood impairments characterized by hippocampal dysfunction (age-related cognitive decline, Autism spectrum disorders, Alzheimer’s disease and PTSD).
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 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, bioRxiv 2021.
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
3. How do properties and connectivity of dentate granule cells causally relate to their encoding and memory functions?
The physiological properties and connectivity of adult-born dentate granule neurons change with their maturation. Computational models have ascribed specific functions for adult-born neurons at different stages of maturation in combination with different circuit elements (interneurons, mossy cells) in mediating these functions. However, empirical and mechanistic evidence are lacking. By identifying genes encoding properties or connectivity with specific circuit elements, we have begun to address these questions using cellular imaging, physiology and behavior. In addition, we are developing strategies to probe stage-specific functions of these genes. Importantly, we will harness these factors (genetically and with small molecules) to assess the impact of discretely reengineering DG-CA3 connectivity to modulate pattern separation-completion balance in adulthood, ageing and in Alzheimer's disease.
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, bioRxiv 2021
5. How do our studies on properties and connectivity of adult-born neurons in rodents inform our thinking of the human brain in health and disease?
We are initiating studies to generate human hippocampal neurons and image DG-CA3 circuit functions in humans to ascertain how properties/connectivity important for encoding functions are conserved between mice and men in health and disease.
6. 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