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Neural circuits for disinhibition in the cerebellum
ABSTRACT Our long-term goal is to understand how the cerebellum adapts and improves movements in response to motor errors. A critical component of this process is signaling from olivary climbing fibers that, by providing strong excitatory drive onto Purkinje cells, induces long-term synaptic plasticity to instantiate corrective adjustments in motor behavior. However, this signaling process is tightly regulated by molecular layer interneurons (MLIs). By strongly inhibiting Purkinje cells, MLIs oppose climbing fiber-driven excitation and gate the induction of corrective plasticity. Thus, for error-driven climbing fiber-induced plasticity and learning to occur effectively, Purkinje cells must undergo disinhibition through the suppression of MLI-mediated input. Notably, MLI ensembles are composed of several subtypes and have a highly structured interconnectivity and are responsive to convergent climbing fiber inputs, suggesting that climbing fiber synchrony- whose functional significance is poorly understood- can selectively engage MLI networks to alter the state of Purkinje cell inhibition. This engagement may balance inhibition and excitation of Purkinje cells during motor errors, creating a circuit mechanism conducive for the acquisition of adaptive learning. The objective of this proposal is to determine how distinct MLI circuits are organized to modulate Purkinje cell excitability through disinhibition in a context-dependent manner, enabling plasticity and learning in response to motor errors. We will employ functional recordings, circuit-targeted activity manipulations, and behavioral analysis to reveal how error-driven instructive signaling emerges from these circuits. In the first aim, we will use in vivo high-density electrophysiology to map functional interactions among MLIs, climbing fibers, and Purkinje cells in the flocculus during the vestibulo-ocular reflex. We will test whether, during motor errors, climbing fibers synchronize their firing to selectively engage disinhibition of Purkinje cells through MLI subtypes in adapting versus non-adapting contexts. In the second aim, we will combine acute slice recordings and molecular anatomy to define direct versus spillover climbing fiber synapses onto MLI subtypes. We will identify synaptic markers and measure climbing-fiber-evoked currents in MLI subtypes, revealing how structural connectivity supports rapid, subtype-specific circuit engagement. In the third aim, we will determine how long-range inputs to the inferior olive, specifically inhibitory projections from the vestibular nuclei, dynamically tune climbing fiber synchrony in vivo and thereby learning through differential engagement of disinhibitory MLI networks. Using functional recording and optogenetic manipulation during the vestibulo- ocular reflex performance, we will establish causal links between climbing fiber synchrony, MLI network state, and adaptive behavior. By fully understanding the logic of instructive signaling, emergent from cerebellar circuit organization and behavioral engagement, we will advance our knowledge of cerebellum-dependent learning processes and provide broader insights into the neural mechanisms of learning and adaptation more generally.
Epigenomic (re)programming of the brain and behavior by ovarian hormones
Rhythmic changes in sex hormone levels across the ovarian cycle exert powerful effects on the brain and behavior, and confer female-specific risks for neuropsychiatric conditions. In this talk, Dr. Kundakovic will discuss the role of fluctuating ovarian hormones as a critical biological factor contributing to the increased depression and anxiety risk in women. Cycling ovarian hormones drive brain and behavioral plasticity in both humans and rodents, and the talk will focus on animal studies in Dr. Kundakovic’s lab that are revealing the molecular and receptor mechanisms that underlie this female-specific brain dynamic. She will highlight the lab’s discovery of sex hormone-driven epigenetic mechanisms, namely chromatin accessibility and 3D genome changes, that dynamically regulate neuronal gene expression and brain plasticity but may also prime the (epi)genome for psychopathology. She will then describe functional studies, including hormone replacement experiments and the overexpression of an estrous cycle stage-dependent transcription factor, which provide the causal link(s) between hormone-driven chromatin dynamics and sex-specific anxiety behavior. Dr. Kundakovic will also highlight an unconventional role that chromatin dynamics may have in regulating neuronal function across the ovarian cycle, including in sex hormone-driven X chromosome plasticity and hormonally-induced epigenetic priming. In summary, these studies provide a molecular framework to understand ovarian hormone-driven brain plasticity and increased female risk for anxiety and depression, opening new avenues for sex- and gender-informed treatments for brain disorders.
Thalamocortical circuits from neuroanatomy to mental representations
In highly volatile environments, performing actions that address current needs and desires is an ongoing challenge for living organisms. For example, the predictive value of environmental signals needs to be updated when predicted and actual outcomes differ. Furthermore, organisms also need to gain control over the environment through actions that are expected to produce specific outcomes. The data to be presented will show that these processes are highly reliant on thalamocortical circuits wherein thalamic nuclei make a critical contribution to adaptive decision-making, challenging the view that the thalamus only acts as a relay station for the cortical stage. Over the past few years, our work has highlighted the specific contribution of multiple thalamic nuclei in the ability to update the predictive link between events or the causal link between actions and their outcomes via the combination of targeted thalamic interventions (lesion, chemogenetics, disconnections) with behavioral procedures rooted in experimental psychology. We argue that several features of thalamocortical architecture are consistent with a prominent role for thalamic nuclei in shaping mental representations.
Associations between brain interoceptive network dysconnectivity and heightened peripheral inflammation in depression
Are the immune system, brain, mind and mood related? Could this explain why chronic low-grade peripheral inflammation is also noted in approximately 1/3 of those with major depressive disorder (MDD)? The field recognized today as immunopsychiatry was founded on scientific evidence that germinated over 30 years ago. Since, it has been understood that (i) there could be a causal link between inflammation and depression, (ii) select blood immune markers show robust potential as biomarkers for inflammation-linked depression, and more generally, (iii) Descartes' theories on mind-body dualism were biologically erroneous. Nonetheless, the mechanistic brain-immune axis in the trinity formulating inflammation-linked depression i.e. psycho-neuro-immunology, still remains unclear. This talk will discuss findings from our recent investigation endeavored to unpack this by linking functional connectivity abnormalities with peripheral immune markers.
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