Assistant Professor of Neurobiology
Neural Circuits, Synaptic Plasticity, Transcription Factors, Gene Regulation, CRISPR/Cas9 Technology, Next Generation Sequencing
The Brigidi Lab is interested in the genomic underpinnings of sensory experience-driven synapse and circuit plasticity. As we explore our surroundings we experience a barrage of sensory stimuli, some salient and most irrelevant, and in response can flexibly update our behavior. How do our brains transform fleeting, salient stimuli into long-lasting memories and behavioral adaptations? How are incoming sensory stimuli transduced at the level of neural circuits and synapses? What molecular mechanisms underlie the plasticity of synapses and circuits necessary for learning and behavioral flexibility?
The most enduring forms of neuronal plasticity require regulation of the genome. Inducible transcription factors (ITFs), a subset of immediate early genes, are rapidly expressed in response to incoming stimuli, traffic into the nucleus and bind thousands of sites across the genome. ITFs carefully orchestrate downstream programs of gene regulation that impact neuronal functions and plasticity, and are therefore poised to tailor a cell's phenotype and role within its local circuit to incoming stimuli in real time and on a continuous basis. The lab's long-term goal is to uncover the genomic mechanisms that form the neural basis of behavioral adaptations, and is investigating key questions surrounding ITF biology:
- Are particular ITFs fine-tuned to specific patterns of depolarizing activity stimuli experienced by neurons within their local circuits? What molecular pathways enable an ITF to distinguish a salient stimulus from an irrelevant one?
- Can ITFs tailor downstream gene regulation programs to a specific stimulus? How do the collection of genes regulated by an ITF impact synaptic and circuit plasticity?
- Is stimulus-specific ITF responsivity and downstream gene regulation also cell subtype-specific? How might ITFs support cellular diversity in neural circuits across brain regions, and through development?
- How does brain region- and cell subtype-specific ITF expression support learning and experience-driven behavioral adaptions?
To answer these questions, the lab uses ex vivo whole-cell electrophysiology with circuit manipulation techniques including pharmacology and optogenetics, combined with biochemistry, new CRISPR/Cas9 technologies, and genome-wide sequencing. Detailed molecular work at the level of intact neural circuits is at the core of all projects within the lab.
- Brigidi GS, Hayes MGB, Delos Santos NP, Hartzell AL, Texari L, Lin P-A, Bartlett A, Ecker JR, Benner C, Heinz S, Bloodgood BL (2019). Genomic decoding of neuronal depolarization by stimulus specific NPAS4 heterodimers. Cell179 :373-391.
- Brigidi GS, Santyr B, Shimmel J, Jovellar B, Bamji SX (2015). Activity-regulated trafficking of the palmitoyl-acyl transferase DHHC5. Nature Communications6:8200.
- Brigidi GS, Sun Y, Beccano-Kelly D, Pitman K, Mobasser M, Borgland SL, Milnerwood AJ, Bamji SX (2014). Palmitoylation of δ-catenin by DHHC5 mediates activity-induced synapse plasticity. Nature Neuroscience17:522-32.
- Shimell JJ, Shah BS, Cain SM, Thouta S, Kuhlmann N, Tatarnikov I, Jovellar DB, Brigidi GS, Kass J, Milnerwood AJ, Snutch TP, Bamji SX (2019). The X-Linked Intellectual Disability Gene Zdhhc9 Is Essential for Dendrite Outgrowth and Inhibitory Synapse Formation. Cell Reports29: P2422-2437.e8
- Hartzell AL, Martyniuk KM, Brigidi GS, Heinz DA, Djaja NA, Payne A, Bloodgood BL (2018). NPAS4 recruits CCK basket cell synapses and enhances cannabinoid-sensitive inhibition in the mouse hippocampus. eLife7:e35927.
- Baronas VA, McGuinness BR, Brigidi GS, Gomm Kolisko RN, Vilin YY, Kim RY, Lynn FC, Bamji SX, Yang R, Kurata HT (2015). Use-dependent activation of neuronal Kv1.2 channel complexes. Journal of Neuroscience35:3515-3524.
- Brigidi GS, Bamji SX (2013). Detection of protein palmitoylation in cultured hippocampal neurons by immunoprecipitation and acyl-biotin exchange (ABE). Journal of Visualized Experiments(72), e50031, (doi:10.3791/50031).
- Mehran AE, Templeman NM, Brigidi GS, Lim GE, Chu KY, Hu X, Botezelli JD, Asadi A, Hoffman BG, Kieffer TJ, Bamji SX, Clee SM, Johnson JD (2012). Hyperinsulinemia drives diet-induced obesity independently of brain insulin production. Cell Metabolism6:723-737.
- Brigidi GS, Bamji SX (2011). Cadherin-catenin adhesion complexes at the synapse. Current Opinion in Neurobiology21:208-214.