Browsing by Author "Calakos, Nicole"
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Item Open Access Exploring the role for mGluR5 in regulating striatal medium spiny neuron development(2016) Bhagat, Srishti BhagatThe striatum is a key brain region for learning and producing movement. Little is known about the molecular mechanisms in the early postnatal period that regulate how medium spiny neurons (MSNs), the predominant cell type in this region, mature. Using electrophysiology in acute brain slices in combination with pharmacological and genetic manipulations of the metabotropic glutamate receptor, mGluR5, I present evidence that mGluR5 may regulate synapse unsilencing. This developmental effect of mGluR5 signaling appears to be modulated by other processes, which I was unable to fully elucidate. However, activation of mGluR5 signaling later in postnatal development is sufficient to reduce excitatory glutamatergic transmission. These data indicate that mGluR5 has important roles in regulating striatal transmission that may be differentially regulated over development.
Item Embargo Mechanisms of Striatal Fast-Spiking Interneuron Plasticity in Habit Learning(2024) Hall, Victoria LThe behavioral transition from goal-directed to habitual responding is known to differentially rely on dorsomedial (DMS) & dorsolateral (DLS) striatal regions; with each region’s activity exerting opposing behavioral influences - DMS activity promoting goal-directed responding and DLS activity required for habitual responding. However, relatively little is known about how local plasticity is expressed within these two regions to mediate the goal to habit behavioral transition. Prior studies establish that fast-spiking interneurons (FSIs) in the dorsolateral striatum (DLS) show experience-dependent plasticity and are required for habitual responding (O'Hare, et al., 2017). FSIs are a sparse cell type within the striatal microcircuitry that exert powerful influence over striatal output in both medial and lateral regions. As of yet, their plasticity in habit has only been studied in DLS, and only in relation to goal-directed subjects, where FSIs in habitual mice show increased excitability relative to goal (O’Hare, et al., 2017).Here, I investigate the state transitions of FSIs in both DMS and DLS across learning goal-directed and habitual responding, beginning with the naïve state. Using lever press instrumental task training, acute brain slice electrophysiological recordings and cell-specific transcriptional profiling, I make three major observations that substantially revise working models and introduce new molecular mechanisms. Although current models support opposing roles for DMS and DLS in goal versus habitual behavior, I find that habit acquisition is accompanied by increased FSI excitability in both regions. By including naïve state physiology, I further reveal that rather than progressive gains in excitability through experience, FSIs instead transition to a temporary state of decreased excitability upon learning an instrumental task in a goal-directed manner. Physiology between FSIs in naïve and habitual subjects were highly similar. Despite similar physiological transitions of FSIs between DMS and DLS regions, I found that the underlying mechanisms are distinct. Electrophysiological, immunohistochemical, and transcriptional data support a model in which DLS FSIs decrease excitability through a transient down-regulation of Kv3 potassium channels and degradation of perineuronal net (PNN) structures; while DMS FSIs reduce excitability through transient increases in parvalbumin (PV) and Ca2+-activated potassium channel expression. My findings substantially revise working models in the field and shift focus away from a model of experience-dependent gains in interneuron plasticity to a model in which early learning imposes a temporary dampening of FSI excitability. In cortical circuits, transient decreases in FSI activity are a well-known gating mechanism to facilitate induction of excitatory synaptic plasticity. My findings suggest that the striatum may use parallel mechanisms, though on distinctly prolonged time scales.
Item Open Access Molecular Mechanisms for Presynaptic Long-term Potentiation(2011) Yang, YingLong-term plasticity, the long-lasting, activity-dependent change in synaptic efficacy, is a fundamental property of the nervous system. Presynaptic forms of long-term plasticity are widely expressed throughout the brain, having been described in regions such as the cortex, cerebellum, hippocampus, thalamus, amygdala and striatum. Presynaptic long-term potentiation (LTP) is associated with an increase in presynaptic release probability, but further evidence of the cellular basis for the change in release probability is not known. At the molecular level, presynaptic LTP is known to require protein kinase A, the synaptic vesicle protein, Rab3A, and the active zone protein, RIM1alpha. RIM1alpha, a presynaptic scaffold protein, binds to many molecules with known functions at different stages of the neurotransmitter release process and the synaptic vesicle cycle. Understanding which interactions of RIM1alpha mediate presynaptic LTP would shed light on the molecular and cellular mechanisms for presynaptic long-term plasticity.
Here I developed a novel platform to achieve robust acute genetic
manipulation of presynaptic proteins at hippocampal mossy fiber synapses, where presynaptic LTP is expressed. With this platform, I perform structure-function analysis of RIM1alpha in presynaptic LTP. I find that RIM1alpha phosphorylation by PKA at serine 413 is not required for mossy fiber LTP, nor does RIM1alpha-Rab3A interation. These findings suggest that RIM1alpha, Rab3A and PKA signaling, instead of functioning synergistically, may represent separate requirements for presynaptic long-term plasticity. I then tested whether Munc13-1, a priming protein, is an effector for RIM1alpha in presynaptic LTP and provide the first evidence for the involvement of Munc13-1 in presynaptic long-term synaptic plasticity. I further demonstrate that the interaction between RIM1alpha and Munc13-1 is required for this plasticity. These results further our understanding of the molecular mechanisms of presynaptic plasticity and suggest that modulation of vesicle priming may provide the cellular substrate for expression of LTP at mossy fiber synapses.
Item Open Access Non-monotonic effects of GABAergic synaptic inputs on neuronal firing.(PLoS computational biology, 2022-06-06) Abed Zadeh, Aghil; Turner, Brandon D; Calakos, Nicole; Brunel, NicolasGABA is generally known as the principal inhibitory neurotransmitter in the nervous system, usually acting by hyperpolarizing membrane potential. However, GABAergic currents sometimes exhibit non-inhibitory effects, depending on the brain region, developmental stage or pathological condition. Here, we investigate the diverse effects of GABA on the firing rate of several single neuron models, using both analytical calculations and numerical simulations. We find that GABAergic synaptic conductance and output firing rate exhibit three qualitatively different regimes as a function of GABA reversal potential, EGABA: monotonically decreasing for sufficiently low EGABA (inhibitory), monotonically increasing for EGABA above firing threshold (excitatory); and a non-monotonic region for intermediate values of EGABA. In the non-monotonic regime, small GABA conductances have an excitatory effect while large GABA conductances show an inhibitory effect. We provide a phase diagram of different GABAergic effects as a function of GABA reversal potential and glutamate conductance. We find that noisy inputs increase the range of EGABA for which the non-monotonic effect can be observed. We also construct a micro-circuit model of striatum to explain observed effects of GABAergic fast spiking interneurons on spiny projection neurons, including non-monotonicity, as well as the heterogeneity of the effects. Our work provides a mechanistic explanation of paradoxical effects of GABAergic synaptic inputs, with implications for understanding the effects of GABA in neural computation and development.Item Open Access Striatal circuit and microcircuit mechanisms for habitual behavior(2017) O'Hare, JustinHabit formation is a behavioral adaptation that automates routine actions. This automation preserves cognitive resources that would otherwise be used to monitor action-outcome relationships. The dorsolateral striatum (DLS), which serves as the brain’s conduit into the basal ganglia, has been implicated in habit formation. However, it was not known whether and how the local DLS circuitry adapts to facilitate habitual behavior. By imaging DLS input-output computations of mice trained in a lever pressing task, I identified pathway-specific features of DLS output that strongly predicted the expression and suppression of habitual behavior. These results demonstrated that DLS actively contributes to the habit memory. To understand how these circuit-level adaptations arise, I then performed a series of ex vivo and in vivo experiments probing the local striatal microcircuitry in the context of habits. I found that a single class of interneuron, the striatal fast-spiking interneuron (FSI), was responsible for these habit-predictive changes in DLS output. I further found that FSIs undergo experience-dependent plasticity with habit formation and that their activity in DLS is required for the expression of habitual behavior. Surprisingly, FSIs also appeared to paradoxically excite physiologically distinct subsets of projection neurons in vivo. Taken together, this body of work outlines a circuit- and microcircuit-level mechanism whereby DLS provides a necessary contribution to the neurobiological underpinnings of habit.
Item Open Access Suitability of Automated Writing Measures for Clinical Trial Outcome in Writer's Cramp.(Movement disorders : official journal of the Movement Disorder Society, 2023-01) Bukhari-Parlakturk, Noreen; Lutz, Michael W; Al-Khalidi, Hussein R; Unnithan, Shakthi; Wang, Joyce En-Hua; Scott, Burton; Termsarasab, Pichet; Appelbaum, Lawrence G; Calakos, NicoleBackground
Writer's cramp (WC) dystonia is a rare disease that causes abnormal postures during the writing task. Successful research studies for WC and other forms of dystonia are contingent on identifying sensitive and specific measures that relate to the clinical syndrome and achieve a realistic sample size to power research studies for a rare disease. Although prior studies have used writing kinematics, their diagnostic performance remains unclear.Objective
This study aimed to evaluate the diagnostic performance of automated measures that distinguish subjects with WC from healthy volunteers.Methods
A total of 21 subjects with WC and 22 healthy volunteers performed a sentence-copying assessment on a digital tablet using kinematic and hand recognition softwares. The sensitivity and specificity of automated measures were calculated using a logistic regression model. Power analysis was performed for two clinical research designs using these measures. The test and retest reliability of select automated measures was compared across repeat sentence-copying assessments. Lastly, a correlational analysis with subject- and clinician-rated outcomes was performed to understand the clinical meaning of automated measures.Results
Of the 23 measures analyzed, the measures of word legibility and peak accelerations distinguished subjects with WC from healthy volunteers with high sensitivity and specificity and demonstrated smaller sample sizes suitable for rare disease studies, and the kinematic measures showed high reliability across repeat visits, while both word legibility and peak accelerations measures showed significant correlations with the subject- and clinician-rated outcomes.Conclusions
Novel automated measures that capture key aspects of the disease and are suitable for use in clinical research studies of WC dystonia were identified. © 2022 International Parkinson and Movement Disorder Society.Item Open Access Transcranial magnetic stimulation: the road to clinical therapy for dystonia(Dystonia) Mulcahey, Patrick J; Peterchev, Angel V; Calakos, Nicole; Bukhari-Parlakturk, NoreenDespite many research studies, transcranial magnetic stimulation (TMS) is not yet an FDA-approved clinical therapy for dystonia patients. This review describes the four major challenges that have historically hindered the clinical translation of TMS. The four challenges described are limited types of clinical trial designs, limited evidence on objective behavioral measures, variability in the TMS clinical response, and the extensive TMS parameters to optimize for clinical therapy. Progress has been made to diversify the types of clinical trial design available to clinical researchers, identify evidence-based objective behavioral measures, and reduce the variability in TMS clinical response. Future studies should identify objective behavioral measures for other dystonia subtypes and expand the optimal TMS stimulation parameters for clinical therapy. Our review highlights the key progress made to overcome these barriers and gaps that remain for TMS to develop into a long-lasting clinical therapy for dystonia patients.