The formation of new episodic memories (what, when and where) requires us to distinguish between similar experiences so that new memories may be stored without interfering with those previously encoded. One neural mechanism by which this is achieved is through pattern separation-completion balance in the dentate gyrus (DG)-CA3 circuit of the hippocampus. Pattern separation is a neural circuit mechanism by which similar inputs are made more divergent at the level of outputs thereby minimizing interference between those similar inputs or memories (try to remember where you parked your car yesterday and the day before in the lot). Pattern completion is a process by which a complete memory is retrieved based on a subset of it's features (an image of a beach brings back memories of a vacation). Studies in rodents and humans have suggested that pattern separation-completion balance is disrupted in aging and in individuals with mild cognitive impairment. Furthermore, we hypothesize that pattern separation-completion imbalance may also underlie the excessive generalization of fear, a hallmark of anxiety disorders such as post-traumatic stress disorder. Since our ability to adaptively respond to the environment is intimately dependent on how efficiently we encode it, pattern separation-completion imbalance may result in abnormal activation of fear and stress circuits in the brain. Thus, pattern separation-completion imbalance may represent a circuit-based endophenotype for these different disorders.
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.
Driven by the goal of rejuvenating and re-engineering DG-CA3 circuitry to enhance cognition and modulate mood, we have undertaken a multifaceted approach that integrates inducible mouse- and viral-genetics, pharmaco- and optogenetics, synaptic tracing, in vivo awake behaving optical imaging, ex vivo electrophysiology and behavioral analysis to ask the following questions. Many of our projects take advantage of nature's evolutionary selected molecular controls (genes) to target discrete elemental features of circuits so as to ascribe casual relationships between connectivity and function.
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 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: Guo et al, manuscript in prep.
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.
Example: Guo et al, Nature Medicine 2018
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 the hippocampus-based processing 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. Example: Raam et al Nature Communications 2017, Besnard et al, Nature Neuroscience 2019
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