Seminars

Neuroplasticity is essential for the establishment and strengthening of neural circuits. Repetitive transcranial magnetic stimulation (rTMS) is commonly used to modulate cortical excitability and shows promise in the treatment of some neurological disorders. Low intensity magnetic stimulation (LI-rTMS), which does not directly elicit action potentials in the stimulated neurons, have also shown some therapeutic effects, and it is important to determine the biological mechanisms underlying the effects of these low intensity magnetic fields, such as would occur in the regions surrounding the central high-intensity focus of rTMS. Our team has used a focal low-intensity (10mT) magnetic stimulation approach to address some of these questions and to identify cellular mechanisms. I will present several studies from our laboratory, addressing (1) effects of LIrTMS on neuronal activity and excitability ; and (2) neuronal morphology and post-lesion repair. The ensemble of our results indicate that the effects of LI-rTMS depend upon the stimulation pattern, the age of the animal, and the presence of cellular magnetoreceptors.

When listening to music, humans readily perceive and move along with a periodic beat. Critically, perception of a periodic beat is commonly elicited by rhythmic stimuli with physical features arranged in a way that is not strictly periodic. Hence, beat perception must capitalize on mechanisms that transform stimulus features into a temporally recurrent format with emphasized beat periodicity. Here, I will present a line of work that aims to clarify the nature and neural basis of this transformation. In these studies, electrophysiological activity was recorded as participants listened to rhythms known to induce perception of a consistent beat across healthy Western adults. The results show that the human brain selectively emphasizes beat representation when it is not acoustically prominent in the stimulus, and this transformation (i) can be captured non-invasively using surface EEG in adult participants, (ii) is already in place in 5- to 6-month-old infants, and (iii) cannot be fully explained by subcortical auditory nonlinearities. Moreover, as revealed by human intracerebral recordings, a prominent beat representation emerges already in the primary auditory cortex. Finally, electrophysiological recordings from the auditory cortex of a rhesus monkey show a significant enhancement of beat periodicities in this area, similar to humans. Taken together, these findings indicate an early, general auditory cortical stage of processing by which rhythmic inputs are rendered more temporally recurrent than they are in reality. Already present in non-human primates and human infants, this "periodized" default format could then be shaped by higher-level associative sensory-motor areas and guide movement in individuals with strongly coupled auditory and motor systems. Together, this highlights the multiplicity of neural processes supporting coordinated musical behaviors widely observed across human cultures.The experiments herein include: a motor timing task comparing the effects of movement vs non-movement with and without feedback (Exp. 1A & 1B), a transcranial magnetic stimulation (TMS) study on the role of the supplementary motor area (SMA) in transforming temporal information (Exp. 2), and a perceptual timing task investigating the effect of noisy movement on time perception with both visual and auditory modalities (Exp. 3A & 3B). Together, the results of these studies support the Bayesian cue combination framework, in that: movement improves the precision of time perception not only in perceptual timing tasks but also motor timing tasks (Exp. 1A & 1B), stimulating the SMA appears to disrupt the transformation of temporal information (Exp. 2), and when movement becomes unreliable or noisy there is no longer an improvement in precision of time perception (Exp. 3A & 3B). Although there is support for the proposed framework, more studies (i.e., fMRI, TMS, EEG, etc.) need to be conducted in order to better understand where and how this may be instantiated in the brain; however, this work provides a starting point to better understanding the intrinsic connection between time and movement

Frequency tagging based on fast periodic visual stimulation (FPVS) provides a window into ongoing visual and cognitive processing and can be leveraged to measure rule learning and high-level categorization. In this talk, I will present data demonstrating highly proficient categorization as living and non-living in preschool children, and characterize the development of this ability during infancy. In addition to associating cognitive functions with development, an intriguing question is whether frequency tagging also captures enduring individual differences, e.g. in general cognitive abilities. First studies indicate high psychometric quality of FPVS categorization responses (XU et al., Dzhelyova), providing a basis for research on individual differences. I will present results from a pilot study demonstrating high correlations between FPVS categorization responses and behavioral measures of processing speed and fluid intelligences. Drawing upon this first evidence, I will discuss the potential of frequency tagging for diagnosing cognitive functions across development.

The hippocampus is a key player in learning and memory. Research into this brain structure has long emphasized its plasticity and flexibility, though recent reports have come to appreciate its remarkably stable firing patterns. How novel information incorporates itself into networks that maintain their ongoing dynamics remains an open question, largely due to a lack of experimental access points into network stability. Development may provide one such access point. To explore this hypothesis, we birthdated CA1 pyramidal neurons using in-utero electroporation and examined their functional features in freely moving, adult mice. We show that CA1 pyramidal neurons of the same embryonic birthdate exhibit prominent cofiring across different brain states, including behavior in the form of overlapping place fields. Spatial representations remapped across different environments in a manner that preserves the biased correlation patterns between same birthdate neurons. These features of CA1 activity could partially be explained by structured connectivity between pyramidal cells and local interneurons. These observations suggest the existence of developmentally installed circuit motifs that impose powerful constraints on the statistics of hippocampal output.

In the central nervous system, neuronal activity is a critical regulator of development and plasticity. Activity-dependent proliferation of healthy glial progenitors, oligodendrocyte precursor cells (OPCs), and the consequent generation of new oligodendrocytes contributes to adaptive myelination. This plasticity of myelin tunes neural circuit function and contributes to healthy cognition. The robust mitogenic effect of neuronal activity on normal oligodendroglial precursor cells, a putative cellular origin for many forms of glioma, suggests that dysregulated or “hijacked” mechanisms of myelin plasticity might similarly promote malignant cell proliferation in this devastating group of brain cancers. Indeed, neuronal activity promotes progression of both high-grade and low-grade glioma subtypes in preclinical models. Crucial mechanisms mediating activity-regulated glioma growth include paracrine secretion of BDNF and the synaptic protein neuroligin-3 (NLGN3). NLGN3 induces multiple oncogenic signaling pathways in the cancer cell, and also promotes glutamatergic synapse formation between neurons and glioma cells. Glioma cells integrate into neural circuits synaptically through neuron-to-glioma synapses, and electrically through potassium-evoked currents that are amplified through gap-junctional coupling between tumor cells This synaptic and electrical integration of glioma into neural circuits is central to tumor progression in preclinical models. Thus, neuron-glial interactions not only modulate neural circuit structure and function in the healthy brain, but paracrine and synaptic neuron-glioma interactions also play important roles in the pathogenesis of glial cancers. The mechanistic parallels between normal and malignant neuron-glial interactions underscores the extent to which mechanisms of neurodevelopment and plasticity are subverted by malignant gliomas, and the importance of understanding the neuroscience of cancer.

SCN8A encodes a major voltage-gated sodium channel expressed in CNS and PNS neurons. Gain-of-function and loss-of-function mutations contribute to human disorders, most notably Developmental and Epileptic Encephalophy (DEE). More than 600 affected individuals have been reported, with the most common mechanism of de novo, gain-of-function mutations. We have developed constitutive and conditional models of gain- and loss- of function mutations in the mouse and characterized the effects of on neuronal firing and neurological phenotypes. Using CRE lines with cellular and developmental specificity, we have probed the effects of activating mutant alleles in various classes of neurons in the developing and adult mouse. Most recently, we are testing genetic therapies that reduce the expression of gain-of-function mutant alleles. We are comparing the effectiveness of allele specific oligos (ASOs), viral delivery of shRNAs, and allele-specific targeting of mutant alleles using Crispr/Cas9 in mouse models of DEE.

Peripersonal space (PPS) defines the portion of space where interactions between our body and the external environment more likely occur. There is no physical boundary defining the PPS with respect to the extrapersonal space, but PPS is continuously constructed by a dedicated neural system integrating external stimuli and tactile stimuli on the body, as a function of their potential interaction. This mechanism represents a primary interface between the individual and the environment. In this talk, I will present most recent evidence and highlight the current debate about the neural and computational mechanisms of PPS, its main functions and properties. I will discuss novel data showing how PPS dynamically shapes to optimize body-environment interactions. I will describe a novel electrophysiological paradigm to study and measure PPS, and show how this has been used to search for a basic marker of potentials of self-environment interaction in newborns and patients with disorders of consciousness. Finally, I will discuss how PPS is also involved in, and in turn shaped by, social interactions. Under these acceptances, I will discuss how PPS plays a key role in self-consciousness.

Our brains must generate and maintain stable activity patterns over decades of life, despite the dramatic changes in circuit connectivity and function induced by learning and experience-dependent plasticity. How do our brains acheive this balance between opposing need for plasticity and stability? Over the past two decades, we and others have uncovered a family of “homeostatic” negative feedback mechanisms that are theorized to stabilize overall brain activity while allowing specific connections to be reconfigured by experience. Here I discuss recent work in which we demonstrate that individual neocortical neurons in freely behaving animals indeed have a homeostatic activity set-point, to which they return in the face of perturbations. Intriguingly, this firing rate homeostasis is gated by sleep/wake states in a manner that depends on the direction of homeostatic regulation: upward-firing rate homeostasis occurs selectively during periods of active wake, while downward-firing rate homeostasis occurs selectively during periods of sleep, suggesting that an important function of sleep is to temporally segregate bidirectional plasticity. Finally, we show that firing rate homeostasis is compromised in an animal model of autism spectrum disorder. Together our findings suggest that loss of homeostatic plasticity in some neurological disorders may render central circuits unable to compensate for the normal perturbations induced by development and learning.

N-methyl-D-aspartate receptors (NMDARs) are excitatory glutamate-gated ion channels that are expressed throughout the central nervous system. NMDARs mediate calcium entry into cells, and are involved in a host of neurological functions. The GluN2A subunit, encoded by the GRIN2A gene, is expressed by both excitatory and inhibitory neurons, with well described roles in pyramidal cells. By using Grin2a knockout mice, we show that the loss of GluN2A signaling impacts parvalbumin-positive (PV) GABAergic interneuron function in hippocampus. Grin2a knockout mice have 33% more PV cells in CA1 compared to wild type but similar cholecystokinin-positive cell density. Immunohistochemistry and electrophysiological recordings show that excess PV cells do eventually incorporate into the hippocampal network and participate in phasic inhibition. Although the morphology of Grin2a knockout PV cells is unaffected, excitability and action-potential firing properties show age-dependent alterations. Preadolescent (P20-25) PV cells have an increased input resistance, longer membrane time constant, longer action-potential half-width, a lower current threshold for depolarization-induced block of action-potential firing, and a decrease in peak action-potential firing rate. Each of these measures are corrected in adulthood, reaching wild type levels, suggesting a potential delay of electrophysiological maturation. The circuit and behavioral implications of this age-dependent PV interneuron malfunction are unknown. However, neonatal Grin2a knockout mice are more susceptible to lipopolysaccharide and febrile-induced seizures, consistent with a critical role for early GluN2A signaling in development and maintenance of excitatory-inhibitory balance. These results could provide insights into how loss-of-function GRIN2A human variants generate an epileptic phenotypes.

Normative development in adolescence indicates that the prefrontal cortex is still under development thereby unable to exert efficient top-down inhibitory control on subcortical regions such as the basolateral amygdala and the nucleus accumbens. This imbalance in the developmental trajectory between cortical and subcortical regions is implicated in expression of the prototypical impulsive, compulsive, reward seeking and risk-taking adolescent behavior. Here we demonstrate that a chronic mild unpredictable stress procedure during adolescence in male Wistar rats arrests the normal behavioral maturation such that they continue to express adolescent-like impulsive, hyperactive, and compulsive behaviors into late adulthood. This arrest in behavioral maturation is associated with the hypoexcitability of prelimbic cortex (PLC) pyramidal neurons and reduced PLC-mediated synaptic glutamatergic control of BLA and nucleus accumbens core (NAcC) neurons that lasts late into adulthood. At the same time stress exposure in adolescence results in the hyperexcitability of the BLA pyramidal neurons sending stronger glutamatergic projections to the NAcC. Chemogenetic reversal of the PLC hypoexcitability decreased compulsivity and improved the expression of goal-directed behavior in rats exposed to stress during adolescence, suggesting a causal role for PLC hypoexcitability in this stress-induced arrested behavioral development. (https://www.biorxiv.org/content/10.1101/2021.11.21.469381v1.abstract)

The Hsieh lab focuses on the mechanisms that promote neural stem cell self-renewal and differentiation in embryonic and adult brain. Using mouse models, video-EEG monitoring, viral techniques, and imaging/electrophysiological approaches, we elucidated many of the key transcriptional/epigenetic regulators of adult neurogenesis and showed aberrant new neuron integration in adult rodent hippocampus contribute to circuit disruption and seizure development. Building on this work, I will present our recent studies describing how GABA-mediated Ca2+ activity regulates the production of aberrant adult-born granule cells. In a new direction of my laboratory, we are using human induced pluripotent stem cells and brain organoid models as approaches to understand brain development and disease. Mutations in one gene, Aristaless-related homeobox (ARX), are of considerable interest since they are known to cause a common spectrum of neurodevelopmental disorders including epilepsy, autism, and intellectual disability. We have generated cortical and subpallial organoids from patients with poly-alanine expansion mutations in ARX. To understand the nature of ARX mutations in the organoid system, we are currently performing cellular, molecular, and physiological analyses. I will present these data to gain a comprehensive picture of the effect of ARX mutations in brain development. Since we do not understand how human brain development is affected by ARX mutations that contribute to epilepsy, we believe these studies will allow us to understand the mechanism of pathogenesis of ARX mutations, which has the potential to impact the diagnosis and care of patients.

Developmental epileptic encephalopathies are early-onset epilepsies, often refractory to therapy, with developmental delay or regression. These disorders carry poor neurodevelopmental prognosis, with long-term refractory epilepsy and persistent cognitive, behavioral and motor deficits. Mutations in the CACNA1A gene, encoding the pore-forming α1 subunit of CaV2.1 voltage-gated calcium channels, result in a spectrum of neurological disorders, including severe, early-onset epileptic encephalopathies. Recent work from the Rossignol lab helped characterize the phenotypic spectrum of CACNA1A-related epilepsies in humans. Using conditional genetics and novel animal models, the Rossignol lab unveiled some of the underlying pathophysiological mechanisms, including critical deficits in cortical inhibition, resulting in seizures and a range of cognitive-behavioral deficits. Importantly, Dr. Rossignol’s team demonstrated that the targeted activation of specific GABAergic interneuron populations in selected cortical regions prevents motor seizures and reverts attention deficits and cognitive rigidity in mouse models of the disorder. These recent findings open novel avenues for the treatment of these severe CACNA1A-associated neurodevelopmental disorders.

Cortical plasticity is the neural mechanism by which the cerebrum adapts itself to its environment, while at the same time making it vulnerable to impoverished sensory or developmental experiences. Like the visual system, auditory development passes through a series of sensitive periods in which circuits and connections are established and then refined by experience. Current research is expanding our understanding of cerebral processing and organization in the deaf. In the congenitally deaf, higher-order areas of "deaf" auditory cortex demonstrate significant crossmodal plasticity with neurons responding to visual and somatosensory stimuli. This crucial cerebral function results in compensatory plasticity. Not only can the remaining inputs reorganize to substitute for those lost, but this additional circuitry also confers enhanced abilities to the remaining systems. In this presentation we will review our present understanding of the structure and function of “deaf” auditory cortex using psychophysical, electrophysiological, and connectional anatomy approaches and consider how this knowledge informs our expectations of the capabilities of cochlear implants in the developing brain.

Dendrites play a central role in neuronal computation, and many complex mechanisms shape their structure, function, and connectivity. Dendrites can undergo plastic changes during development and learning, as well as during neurodevelopmental and neurodegenerative disease. We will discuss how the molecular and electrophysiological properties of dendrites enable them to perform complex computations important for sensory-motor processing and higher cognitive function, and how these can go awry.

Broadly, the Mauro Costa-Mattioli laboratory (The MCM Lab) encompasses two complementary lines of research. The first one, more traditional but very important, aims at unraveling the molecular mechanisms underlying memory formation (e.g., using state-of-the-art molecular and cell-specific genetic approaches). Learning and memory disorders can strike the brain during development (e.g., Autism Spectrum Disorders and Down Syndrome), as well as during adulthood (e.g., Alzheimer’s disease). We are interested in understanding the specific circuits and molecular pathways that are primarily targeted in these disorders and how they can be restored. To tackle these questions, we use a multidisciplinary, convergent and cross-species approach that combines mouse and fly genetics, molecular biology, electrophysiology, stem cell biology, optogenetics and behavioral techniques. The second line of research, more recent and relatively unexplored, is focused on understanding how gut microbes control CNS driven-behavior and brain function. Our recent discoveries, that microbes in the gut could modulate brain function and behavior in a very powerful way, have added a whole new dimension to the classic view of how complex behaviors are controlled. The unexpected findings have opened new avenues of study for us and are currently driving my lab to answer a host of new and very interesting questions: - What are the gut microbes (and metabolites) that regulate CNS-driven behaviors? Would it be possible to develop an unbiased screening method to identify specific microbes that regulate different behaviors? - If this is the case, can we identify how members of the gut microbiome (and their metabolites) mechanistically influence brain function? - What is the communication channel between the gut microbiota and the brain? Do different gut microbes use different ways to interact with the brain? - Could disruption of the gut microbial ecology cause neurodevelopmental dysfunction? If so, what is the impact of disruption in young and adult animals? - More importantly, could specific restoration of selected bacterial strains (new generation probiotics) represent a novel therapeutic approach for the targeted treatment of neurodevelopmental disorders? - Finally, can we develop microbiota-directed therapeutic foods to repair brain dysfunction in a variety of neurological disorders?

The developmental journey of cortical interneurons encounters several activity-dependent milestones. During the early postnatal period in developing mice, GABAergic neurons are transient preferential recipients of thalamic inputs and undergo activity-dependent migration arrest, wiring and programmed cell-death. But cortical GABAergic neurons are also specified by very early developmental programs. For example, the earliest born GABAergic neurons develop into hub cells coordinating spontaneous activity in hippocampal slices. Despite their importance for the emergence of sensory experience, their role in coordinating network dynamics, and the role of activity in their integration into cortical networks, the collective in vivo dynamics of GABAergic neurons during the neonatal postnatal period remain unknown. Here, I will present data related to the coordinated activity between GABAergic cells of the mouse barrel cortex and hippocampus in non-anesthetized pups using the recent development of all optical methods to record and manipulate neuronal activity in vivo. I will show that the functional structure of developing GABAergic circuits is remarkably patterned, with segregated assemblies of prospective parvalbumin neurons and highly connected hub cells, both shaped by sensory-dependent processes.

Dravet syndrome (DS) is a neurodevelopmental disorder caused by heterozygous loss-of-function of the gene SCN1A encoding the voltage-gated sodium channel subunit Nav1.1, and is defined by treatment-resistant epilepsy, intellectual impairment, and sudden death. However, disease mechanisms remain unclear, as previously-identified deficiency in action potential generation of Nav1.1-expressing parvalbumin-positive fast-spiking GABAergic interneurons (PV-INs) in DS (Scn1a+/-) mice normalizes during development. We used a novel approach that facilitated the assessment of PV-IN function at both early (post-natal day (P) 16-21) and late (P35-56) time points in the same mice. We confirmed that PV-IN spike generation was impaired at P16-21 in all mice (those deceased from SUDEP by P35 and those surviving to P35-56). However, unitary synaptic transmission assessed in PV-IN:principal cell paired recordings was severely dysfunctional selectively in mice recorded at P16-21 that did not survive to P35. Spike generation in surviving mice had normalized by P35-56; yet we again identified abnormalities in synaptic transmission in surviving mice. We propose that early dysfunction of PV-IN spike propagation drives epilepsy severity and risk of sudden death, while persistent dysfunction of spike propagation contributes to chronic DS pathology.