Regulation of cortical circuit maturation and plasticity by oligodendrocytes and myelin

Targeting gamma oscillations to improve cognition

Neurovascular Interactions: Mechanisms, Imaging, Therapeutics

Adaptive deep brain stimulation to treat gait disorders in Parkinson's disease; Personalized chronic adaptive deep brain stimulation outperforms conventional stimulation in Parkinson's disease

On Friday, August 31st we will host Stephanie Cernera & Doris Wang! Stephanie Cernera, PhD, is a postdoctoral research fellow in the Starr lab at University of California San Francisco. She will tell us about “Personalized chronic adaptive deep brain stimulation outperforms conventional stimulation in Parkinson’s Disease”. Doris Wang, MD, PhD, is a neurosurgeon and assistant professor at the University of California San Francisco. Apart from her scientific presentation about “Adaptive Deep Brain Stimulation to Treat Gait Disorders in Parkinson’s Disease”, she will give us a glimpse at the “Person behind the science”. The talks will be followed by a shared discussion. You can register via talks.stimulatingbrains.org to receive the (free) Zoom link!

Homeostatic Plasticity in Health and Disease

Dr. Davis will present a summary regarding the identification and characterization of mechanisms of homeostatic plasticity as they relate to the control of synaptic transmission. He will then provide evidence of translation to the mammalian neuromuscular junction and central synapses, and provide tangible links to the etiology of neurological disease.

Brain-body interactions that modulate fear

In most animals including in humans, emotions occur together with changes in the body, such as variations in breathing or heart rate, sweaty palms, or facial expressions. It has been suggested that this interoceptive information acts as a feedback signal to the brain, enabling adaptive modulation of emotions that is essential for survival. As such, fear, one of our basic emotions, must be kept in a functional balance to minimize risk-taking while allowing for the pursuit of essential needs. However, the neural mechanisms underlying this adaptive modulation of fear remain poorly understood. In this talk, I want to present and discuss the data from my PhD work where we uncover a crucial role for the interoceptive insular cortex in detecting changes in heart rate to maintain an equilibrium between the extinction and maintenance of fear memories in mice.

Norepinephrine links astrocytic activity to regulation of cortical state

Cortical state, defined by the synchrony of population-level neuronal activity, is a key determinant of sensory perception. While many arousal-associated neuromodulators—including norepinephrine (NE)—reduce cortical synchrony, how the cortex resynchronizes following NE signaling remains unknown. Using in vivo two-photon imaging and electrophysiology in mouse visual cortex, we describe a critical role for cortical astrocytes in circuit resynchronization. We characterize astrocytes’ sensitive calcium responses to changes in behavioral arousal and NE, identify that astrocyte signaling precedes increases in cortical synchrony, and demonstrate that astrocyte-specific deletion of Adra1A alters arousal-related cortical synchrony. Our findings demonstrate that astrocytic NE signaling acts as a distinct neuromodulatory pathway, regulating cortical state and linking arousal-associated desynchrony to cortical circuit resynchronization.

Hippocampal replay reflects specific past experiences rather than a plan for subsequent choice

Executing memory-guided behavior requires storage of information about experience and later recall of that information to inform choices. Awake hippocampal replay, when hippocampal neural ensembles briefly reactivate a representation related to prior experience, has been proposed to critically contribute to these memory-related processes. However, it remains unclear whether awake replay contributes to memory function by promoting the storage of past experiences, facilitating planning based on evaluation of those experiences, or both. We designed a dynamic spatial task that promotes replay before a memory-based choice and assessed how the content of replay related to past and future behavior. We found that replay content was decoupled from subsequent choice and instead was enriched for representations of previously rewarded locations and places that had not been visited recently, indicating a role in memory storage rather than in directly guiding subsequent behavior.

Mature retina is resilient to partial photoreceptor loss

I will discuss recent findings from our lab about the effects of partial photoreceptor loss on the retinal circuit’s structure and function. I will relate this work to the question of whether the visual system can distinguish between changes in light level and photoreceptor number.

Pediatric Migraine: Who, What, When, Where

This talk will address important aspects of pediatric migraine research, including: 1) Who is affected by pediatric migraine? 2) What does pediatric migraine look like, and what does a clinician need to do to reach a migraine diagnosis in a child? 3) When does pediatric migraine begin, and how might it present clinically before it presents as headache (e.g., infant colic, benign paroxysmal torticollis, cyclic vomiting syndrome etc.) 4) Where does responsibility for decreasing pediatric migraine frequency rest? What is society's role in preventing migraine in young people?

The role of the complement pathway in post-traumatic sleep disruption and epilepsy

While traumatic brain injury (TBI) acutely disrupts the cortex, most TBI-related disabilities reflect secondary injuries that accrue over time. The thalamus is a likely site of secondary damage because of its reciprocal connections with the cortex. Using a mouse model of mild cortical injury that does not directly damage subcortical structures (mTBI), we found a chronic increase in C1q expression specifically in the corticothalamic circuit. Increased C1q expression co-localized with neuron loss and chronic inflammation, and correlated with disruption in sleep spindles and emergence of epileptic activities. Blocking C1q counteracted these outcomes, suggesting that C1q is a disease modifier in mTBI. Single-nucleus RNA sequencing demonstrated that microglia are the source of thalamic C1q. Since the corticothalamic circuit is important for cognition and sleep, which can be impaired by TBI, this circuit could be a new target for treating TBI-related disabilities

Microglia, memories, and the extracellular space

Microglia are the immune cells of the brain, and play increasingly appreciated roles in synapse formation, brain plasticity, and cognition. A growing appreciation that the immune system involved in diseases like schizophrenia, epilepsy, and neurodegenerative diseases has led to renewed interest in how microglia regulate synaptic connectivity. Our group previously identified the IL-1 family cytokine Interleukin-33 (IL-33) as a novel regulator of microglial activation and function. I will discuss a mechanism by which microglia regulate synaptic plasticity and long-term memories by engulfing brain extracellular matrix (ECM) proteins. These studies raise the question of how these pathways may be altered or could be modified in the context of disease.

Functional characterization and therapeutic targeting of gene regulatory elements

Homeostatic Plasticity in Health and Disease

Sodium channel dysfunction in neurodevelopmental disorders

CRISPR-based functional genomics in iPSC-based models of brain disease

Human genes associated with brain-related diseases are being discovered at an accelerating pace. A major challenge is an identification of the mechanisms through which these genes act, and of potential therapeutic strategies. To elucidate such mechanisms in human cells, we established a CRISPR-based platform for genetic screening in human iPSC-derived neurons, astrocytes and microglia. Our approach relies on CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa), in which a catalytically dead version of the bacterial Cas9 protein recruits transcriptional repressors or activators, respectively, to endogenous genes to control their expression, as directed by a small guide RNA (sgRNA). Complex libraries of sgRNAs enable us to conduct genome-wide or focused loss-of-function and gain-of-function screens. Such screens uncover molecular players for phenotypes based on survival, stress resistance, fluorescent phenotypes, high-content imaging and single-cell RNA-Seq. To uncover disease mechanisms and therapeutic targets, we are conducting genetic modifier screens for disease-relevant cellular phenotypes in patient-derived neurons and glia with familial mutations and isogenic controls. In a genome-wide screen, we have uncovered genes that modulate the formation of disease-associated aggregates of tau in neurons with a tauopathy-linked mutation (MAPT V337M). CRISPRi/a can also be used to model and functionally evaluate disease-associated changes in gene expression, such as those caused by eQTLs, haploinsufficiency, or disease states of brain cells. We will discuss an application to Alzheimer’s Disease-associated genes in microglia.