therapeutic interventions

Intrinsic and extrinsic mechanisms underlying trigeminal nerve deficits in familial dysautonomia

PROJECT SUMMARY Rare diseases impose a significant burden on the US healthcare system, accounting for nearly half of all expenditures for their treatment. This statistic alone supports the need to invest in research to develop therapeutic interventions for rare diseases since the economic benefit outweighs the continued expense of financial resources. Familial dysautonomia (FD) is a rare, hereditary disease that arises from a splice site mutation in Elongator acetyltransferase complex subunit 1 (ELP1) and impacts the nervous system. To date, FD patients continue to face life-threatening complications involving basic involuntary functions like swallowing and somatosensation because there is no cure for this ultimately fatal neuropathy. FD patients exhibit symptoms due to defects in their somatosensory trigeminal nerves, whose cell bodies reside in the trigeminal ganglion (TG) and are derived from neural crest and placode cells. Recent studies from our lab using an FD mouse model (Elp1 deleted from neural crest cells) revealed TG axon outgrowth and target tissue innervation deficits, recapitulating phenotypes observed in FD patients. However, the mechanisms by which Elp1 mediates normal TG development, and how this goes awry in FD, remain largely elusive. To gain insight into Elp1 function, we performed mass spectrometry to evaluate the TG proteome of normal and FD mouse embryos. Our results uncovered statistically significant increases in extracellular matrix (ECM) and ECM binding proteins, pointing to altered TG biomechanical properties and, more broadly, changes in mechanotransduction, the process by which cells translate extrinsic cues into intrinsic signaling pathways that modulate gene expression. Importantly, proper axon outgrowth relies upon mechanotransduction as growth cones on axons sense and respond to their environment. In the head, this environment consists of ECM and cranial mesenchyme cells, but the impact of Elp1 loss from the latter is not known, including the potential for altered tissue biomechanics that could influence TG axon outgrowth. We hypothesize that loss of Elp1 induces changes in the biomechanical properties of both the TG/nerves and ECM/cranial mesenchyme, modifying mechanotransduction and leading to TG defects in FD, which we will interrogate in the following Specific Aims: 1) define the biomechanical properties of the TG/nerves and ECM/cranial mesenchyme and 2) determine the role of cranial mesenchyme Elp1 in mediating proper TG axon outgrowth. Our innovative research proposal takes a systems-level, multidisciplinary approach involving embryology, biomechanics, and high-resolution microscopy, with the goal of integrating molecular, cellular, and tissue data. These results will significantly advance our knowledge of the molecular mechanisms underscoring TG development and, collectively, inform treatment strategies for birth defects or disorders like FD with TG dysfunction, as well as nerve repair and/or regeneration after injury or disease.

Organization of thalamic networks and mechanisms of dysfunction in schizophrenia and autism

Thalamic networks, at the core of thalamocortical and thalamosubcortical communications, underlie processes of perception, attention, memory, emotions, and the sleep-wake cycle, and are disrupted in mental disorders, including schizophrenia and autism. However, the underlying mechanisms of pathology are unknown. I will present novel evidence on key organizational principles, structural, and molecular features of thalamocortical networks, as well as critical thalamic pathway interactions that are likely affected in disorders. This data can facilitate modeling typical and abnormal brain function and can provide the foundation to understand heterogeneous disruption of these networks in sleep disorders, attention deficits, and cognitive and affective impairments in schizophrenia and autism, with important implications for the design of targeted therapeutic interventions

Microbial modulation of zebrafish behavior and brain development

There is growing recognition that host-associated microbiotas modulate intrinsic neurodevelopmental programs including those underlying human social behavior. Despite this awareness, the fundamental processes are generally not understood. We discovered that the zebrafish microbiota is necessary for normal social behavior. By examining neuronal correlates of behavior, we found that the microbiota restrains neurite complexity and targeting of key forebrain neurons within the social behavior circuitry. The microbiota is also necessary for both localization and molecular functions of forebrain microglia, brain-resident phagocytes that remodel neuronal arbors. In particular, the microbiota promotes expression of complement signaling pathway components important for synapse remodeling. Our work provides evidence that the microbiota modulates zebrafish social behavior by stimulating microglial remodeling of forebrain circuits during early neurodevelopment and suggests molecular pathways for therapeutic interventions during atypical neurodevelopment.

Causal Symptom Network Mapping Based on Lesions and Brain Stimulation; Converging Evidence about a Depression Circuit Using Causal Sources of Information

It’s our pleasure to announce that we will host Shan Siddiqi and Michael D. Fox on Thursday, March 30th at noon ET / 6PM CET. Shan Siddiqi, MD, is an Assistant Professor of Psychiatry at Harvard Medical School and the director of Psychiatric Neuromodulation Research at the Brigham and Women’s Hospital. Michael D. Fox, MD, PhD, is an Associate Professor of Neurology at Harvard Medical School and the founding director of the Center for Brain Circuit Therapeutics at the Brigham and Women’s Hospital. The talks will be followed by a shared discussion. You can register via talks.stimulatingbrains.org to receive the (free) Zoom link!

Primary Motor Cortex Circuitry in a Mouse Model of Parkinson’s Disease

The primary motor cortex (M1) is a major output center for movement execution and motor learning, and its dysfunction contributes to the pathophysiology of Parkinson’s disease (PD). While human studies have indicated that a loss of midbrain dopamine neurons alters M1 activation, the mechanisms underlying this phenomenon remain unclear. Using a mouse model of PD, we uncovered several shifts within M1 circuitry following dopamine depletion, including impaired excitation by thalamocortical afferents and altered excitability. Our findings add to the growing body of literature highlighting M1 as a major contributor in PD, and provide targeted neural substrates for possible therapeutic interventions.

Playing fast and loose with glutamate builds healthy circuits in the developing cortex

The construction of cortical circuits requires the precise formation of connections between excitatory and inhibitory neurons during early development. Multiple factors, including neurotransmitters, neuronal activity, and neuronal-glial interactions, shape how these critical circuits form. Disruptions of these early processes can disrupt circuit formation, leading to epilepsy and other neurodevelopmental disorders. Here, I will describe our work into understanding how prolonged post-natal astrocyte development in the cortex creates a permissive window for glutamate signaling that provides tonic activation of developing interneurons through Grin2D NMDA receptors. Experimental disruption of this pathway results in hyperexcitable cortical circuits and human mutations in the Grin2D gene, as well as other related molecules that regulate early life glutamate signaling, are associated with devastating epileptic encephalopathies. We will explore fundamental mechanisms linking early life glutamate signaling and later circuit hyperexcitability, with an emphasis on potential therapeutic interventions aimed at reducing epilepsy and other neurological dysfunction.

Toward novel therapeutic interventions for STXBP1-associated disorders