Non-invasive human neuroimaging studies of motor plasticity have predominantly focused on the cerebral cortex due to low signal-to-noise ration of blood oxygen level-dependent (BOLD) signals in subcortical structures and the small effect sizes typically observed in plasticity paradigms. Precision functional mapping can help overcome these challenges and has revealed significant and reversible functional alterations in the cortico-subcortical motor circuit during arm immobilization

Mitochondrial diversity in the mouse and human brain

The basis of the mind, of mental states, and complex behaviors is the flow of energy through microscopic and macroscopic brain structures. Energy flow through brain circuits is powered by thousands of mitochondria populating the inside of every neuron, glial, and other nucleated cell across the brain-body unit. This seminar will cover emerging approaches to study the mind-mitochondria connection and present early attempts to map the distribution and diversity of mitochondria across brain tissue. In rodents, I will present convergent multimodal evidence anchored in enzyme activities, gene expression, and animal behavior that distinct behaviorally-relevant mitochondrial phenotypes exist across large-scale mouse brain networks. Extending these findings to the human brain, I will present a developing systematic biochemical and molecular map of mitochondrial variation across cortical and subcortical brain structures, representing a foundation to understand the origin of complex energy patterns that give rise to the human mind.

Sampling the environment with body-brain rhythms

Since Darwin, comparative research has shown that most animals share basic timing capacities, such as the ability to process temporal regularities and produce rhythmic behaviors. What seems to be more exclusive, however, are the capacities to generate temporal predictions and to display anticipatory behavior at salient time points. These abilities are associated with subcortical structures like basal ganglia (BG) and cerebellum (CE), which are more developed in humans as compared to nonhuman animals. In the first research line, we investigated the basic capacities to extract temporal regularities from the acoustic environment and produce temporal predictions. We did so by adopting a comparative and translational approach, thus making use of a unique EEG dataset including 2 macaque monkeys, 20 healthy young, 11 healthy old participants and 22 stroke patients, 11 with focal lesions in the BG and 11 in the CE. In the second research line, we holistically explore the functional relevance of body-brain physiological interactions in human behavior. Thus, a series of planned studies investigate the functional mechanisms by which body signals (e.g., respiratory and cardiac rhythms) interact with and modulate neurocognitive functions from rest and sleep states to action and perception. This project supports the effort towards individual profiling: are individuals’ timing capacities (e.g., rhythm perception and production), and general behavior (e.g., individual walking and speaking rates) influenced / shaped by body-brain interactions?

Binocular combination of light

The brain combines signals across the eyes. This process is well-characterized for the perceptual anatomical pathway through V1 that primarily codes contrast, where interocular normalization ensures that responses are approximately equal for monocular and binocular stimulation. But we have much less understanding of how luminance is combined binocularly, both in the cortex and in subcortical structures that govern pupil diameter. Here I will describe the results of experiments using a novel combined EEG and pupillometry paradigm to simultaneously index binocular combination of luminance flicker in parallel pathways. The results show evidence of a more linear process than for spatial contrast, that may reflect different operational constraints in distinct anatomical pathways.

Neural circuits for novel choices and for choice speed and accuracy changes in macaques

While most experimental tasks aim at isolating simple cognitive processes to study their neural bases, naturalistic behaviour is often complex and multidimensional. I will present two studies revealing previously uncharacterised neural circuits for decision-making in macaques. This was possible thanks to innovative experimental tasks eliciting sophisticated behaviour, bridging the human and non-human primate research traditions. Firstly, I will describe a specialised medial frontal circuit for novel choice in macaques. Traditionally, monkeys receive extensive training before neural data can be acquired, while a hallmark of human cognition is the ability to act in novel situations. I will show how this medial frontal circuit can combine the values of multiple attributes for each available novel item on-the-fly to enable efficient novel choices. This integration process is associated with a hexagonal symmetry pattern in the BOLD response, consistent with a grid-like representation of the space of all available options. We prove the causal role played by this circuit by showing that focussed transcranial ultrasound neuromodulation impairs optimal choice based on attribute integration and forces the subjects to default to a simpler heuristic decision strategy. Secondly, I will present an ongoing project addressing the neural mechanisms driving behaviour shifts during an evidence accumulation task that requires subjects to trade speed for accuracy. While perceptual decision-making in general has been thoroughly studied, both cognitively and neurally, the reasons why speed and/or accuracy are adjusted, and the associated neural mechanisms, have received little attention. We describe two orthogonal dimensions in which behaviour can vary (traditional speed-accuracy trade-off and efficiency) and we uncover independent neural circuits concerned with changes in strategy and fluctuations in the engagement level. The former involves the frontopolar cortex, while the latter is associated with the insula and a network of subcortical structures including the habenula.

The pervasive role of visuospatial coding

Historically, retinotopic organisation (the spatial mapping of the retina across the cortical surface) was considered the purview of early regions of visual cortex (V1-V4) only and that anterior, more cognitively involved regions abstracted this information away. The contemporary view is quite different. Here, with Advancing technologies and analysis methods, we see that retinotopic information is not simply thrown away by these regions but rather is maintained to the potential benefit of our broader cognition. This maintenance of visuospatial coding extends not only through visual cortex, but is present in parietal, frontal, medial and subcortical structures involved with coordinating-movements, mind-wandering and even memory. In this talk, I will outline some of the key empirical findings from my own work and the work of others that shaped this contemporary perspective.

Functional ultrasound imaging during behavior

The dream of a systems neuroscientist is to be able to unravel neural mechanisms that give rise to behavior. It is increasingly appreciated that behavior involves the concerted distributed activity of multiple brain regions so the focus on single or few brain areas might hinder our understanding. There have been quite a few technological advancements in this domain. Functional ultrasound imaging (fUSi) is an emerging technique that allows us to measure neural activity from medial frontal regions down to subcortical structures up to a depth of 20 mm. It is a method for imaging transient changes in cerebral blood volume (CBV), which are proportional to neural activity changes. It has excellent spatial resolution (~100 μm X 100 μm X 400 μm); its temporal resolution can go down to 100 milliseconds. In this talk, I will present its use in two model systems: marmoset monkeys and rats. In marmoset monkeys, we used it to delineate a social – vocal network involved in vocal communication while in rats, we used it to gain insights into brain wide networks involved in evidence accumulation based decision making. fUSi has the potential to provide an unprecedented access to brain wide dynamics in freely moving animals performing complex behavioral tasks.

The role of the complement pathway in post-traumatic sleep disruption and epilepsy

While traumatic brain injury (TBI) acutely disrupts the cortex, most TBI-related disabilities reflect secondary injuries that accrue over time. The thalamus is a likely site of secondary damage because of its reciprocal connections with the cortex. Using a mouse model of mild cortical injury that does not directly damage subcortical structures (mTBI), we found a chronic increase in C1q expression specifically in the corticothalamic circuit. Increased C1q expression co-localized with neuron loss and chronic inflammation, and correlated with disruption in sleep spindles and emergence of epileptic activities. Blocking C1q counteracted these outcomes, suggesting that C1q is a disease modifier in mTBI. Single-nucleus RNA sequencing demonstrated that microglia are the source of thalamic C1q. Since the corticothalamic circuit is important for cognition and sleep, which can be impaired by TBI, this circuit could be a new target for treating TBI-related disabilities

A metabolic function of the hippocampal sharp wave-ripple

The hippocampal formation has been implicated in both cognitive functions as well as the sensing and control of endocrine states. To identify a candidate activity pattern which may link such disparate functions, we simultaneously measured electrophysiological activity from the hippocampus and interstitial glucose concentrations in the body of freely behaving rats. We found that clusters of sharp wave-ripples (SPW-Rs) recorded from both dorsal and ventral hippocampus reliably predicted a decrease in peripheral glucose concentrations within ~10 minutes. This correlation was less dependent on circadian, ultradian, and meal-triggered fluctuations, it could be mimicked with optogenetically induced ripples, and was attenuated by pharmacogenetically suppressing activity of the lateral septum, the major conduit between the hippocampus and subcortical structures. Our findings demonstrate that a novel function of the SPW-R is to modulate peripheral glucose homeostasis and offer a mechanism for the link between sleep disruption and blood glucose dysregulation seen in type 2 diabetes and obesity.

Cortical and subcortical grey matter micro-structure is associated with polygenic risk for schizophrenia

Background: Recent discovery of hundreds of common gene variants associated with schizophrenia has enabled polygenic risk scores (PRS) to be measured in the population. It is hypothesized that normal variation in genetic risk of schizophrenia should be associated with MRI changes in brain morphometry and tissue composition. Methods: We used the largest extant genome-wide association dataset (N = 69,369 cases and N = 236,642 healthy controls) to measure PRS for schizophrenia in a large sample of adults from the UK Biobank (Nmax = 29,878) who had multiple micro- and macro-structural MRI metrics measured at each of 180 cortical areas and seven subcortical structures. Linear mixed effect models were used to investigate associations between schizophrenia PRS and brain structure at global and regional scales, controlled for multiple comparisons. Results: Micro-structural phenotypes were more robustly associated with schizophrenia PRS than macro-structural phenotypes. Polygenic risk was significantly associated with reduced neurite density index (NDI) at global brain scale, at 149 cortical regions, and five subcortical structures. Other micro-structural parameters, e.g., fractional anisotropy, that were correlated with NDI were also significantly associated with schizophrenia PRS. Genetic effects on multiple MRI phenotypes were co-located in temporal, cingulate and prefrontal cortical areas, insula, and hippocampus. (Preprint: https://www.medrxiv.org/content/10.1101/2021.02.06.21251073v1)

The interaction of sensory and motor information to shape neuronal representations in mouse cortical networks

The neurons in our brain never function in isolation; they are organized into complex circuits which perform highly specialized information processing tasks and transfer information through large neuronal networks. The aim of Janelle Pakan's research group is to better understand how neural circuits function during the transformation of information from sensory perception to behavioural output. Importantly, they also aim to further understand the cell-type specific processes that interrupt the flow of information through neural circuits in neurodegenerative disorders with dementia. The Pakan group utilizes innovative neuroanatomical tracing techniques, advanced in vivo two-photon imaging, and genetically targeted manipulations of neuronal activity to investigate the cell-type specific microcircuitry of the cerebral cortex, the macrocircuitry of cortical output to subcortical structures, and the functional circuitry underlying processes of sensory perception and motor behaviour.

Circuit mechanisms underlying the dynamic control of cortical processing by subcortical neuromodulators

Behavioral states such as arousal and attention can have profound effects on sensory processing, determining how – sometimes whether – a stimulus is processed. This state-dependence is believed to arise, at least in part, as a result of inputs to cortex from subcortical structures that release neuromodulators such as acetylcholine, noradrenaline, and serotonin, often non-synaptically. The mechanisms that underlie the interaction between these “wireless” non-synaptic signals and the “wired” cortical circuit are not well understood. Furthermore, neuromodulatory signaling is traditionally considered broad in its impact across cortex (within a species) and consistent in its form and function across species (at least in mammals). The work I will present approaches the challenge of understanding neuromodulatory action in the cortex from a number of angles: anatomy, physiology, pharmacology, and chemistry. The overarching goal of our effort is to elucidate the mechanisms behind local neuromodulation in the cortex of non-human primates, and to reveal differences in structure and function across cortical model systems.

Single-cell volumetric transcriptomic atlas of the adult zebrafish forebrain reveals teleost homologues of cortical and subcortical structures from terrestrial vertebrates

FENS Forum 2024