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Brain : a Journal of Neurology Oct 2022Epilepsy is well-recognized as a disorder of brain networks. There is a growing body of research to identify critical nodes within dynamic epileptic networks with the... (Review)
Review
Epilepsy is well-recognized as a disorder of brain networks. There is a growing body of research to identify critical nodes within dynamic epileptic networks with the aim to target therapies that halt the onset and propagation of seizures. In parallel, intracranial neuromodulation, including deep brain stimulation and responsive neurostimulation, are well-established and expanding as therapies to reduce seizures in adults with focal-onset epilepsy; and there is emerging evidence for their efficacy in children and generalized-onset seizure disorders. The convergence of these advancing fields is driving an era of 'network-guided neuromodulation' for epilepsy. In this review, we distil the current literature on network mechanisms underlying neurostimulation for epilepsy. We discuss the modulation of key 'propagation points' in the epileptogenic network, focusing primarily on thalamic nuclei targeted in current clinical practice. These include (i) the anterior nucleus of thalamus, now a clinically approved and targeted site for open loop stimulation, and increasingly targeted for responsive neurostimulation; and (ii) the centromedian nucleus of the thalamus, a target for both deep brain stimulation and responsive neurostimulation in generalized-onset epilepsies. We discuss briefly the networks associated with other emerging neuromodulation targets, such as the pulvinar of the thalamus, piriform cortex, septal area, subthalamic nucleus, cerebellum and others. We report synergistic findings garnered from multiple modalities of investigation that have revealed structural and functional networks associated with these propagation points - including scalp and invasive EEG, and diffusion and functional MRI. We also report on intracranial recordings from implanted devices which provide us data on the dynamic networks we are aiming to modulate. Finally, we review the continuing evolution of network-guided neuromodulation for epilepsy to accelerate progress towards two translational goals: (i) to use pre-surgical network analyses to determine patient candidacy for neurostimulation for epilepsy by providing network biomarkers that predict efficacy; and (ii) to deliver precise, personalized and effective antiepileptic stimulation to prevent and arrest seizure propagation through mapping and modulation of each patients' individual epileptogenic networks.
Topics: Adult; Child; Humans; Deep Brain Stimulation; Anticonvulsants; Epilepsy; Subthalamic Nucleus; Thalamus; Epilepsies, Partial
PubMed: 35771657
DOI: 10.1093/brain/awac234 -
Nature Neuroscience Feb 2022The thalamus engages in various functions including sensory processing, attention, decision making and memory. Classically, this diversity of function has been... (Review)
Review
The thalamus engages in various functions including sensory processing, attention, decision making and memory. Classically, this diversity of function has been attributed to the nuclear organization of the thalamus, with each nucleus performing a well-defined function. Here, we highlight recent studies that used state-of-the-art expression profiling, which have revealed gene expression gradients at the single-cell level within and across thalamic nuclei. These gradients, combined with anatomical tracing and physiological analyses, point to previously unappreciated heterogeneity and redefine thalamic units of function on the basis of unique input-output connectivity patterns and gene expression. We propose that thalamic subnetworks, defined by the intersection of genetics, connectivity and computation, provide a more appropriate level of functional description; this notion is supported by behavioral phenotypes resulting from appropriately tailored perturbations. We provide several examples of thalamic subnetworks and suggest how this new perspective may both propel progress in basic neuroscience and reveal unique targets with therapeutic potential.
Topics: Attention; Neural Pathways; Thalamic Nuclei; Thalamus
PubMed: 35102334
DOI: 10.1038/s41593-021-00996-1 -
Cell Sep 2022Computational analysis of cellular activity has developed largely independently of modern transcriptomic cell typology, but integrating these approaches may be essential...
Computational analysis of cellular activity has developed largely independently of modern transcriptomic cell typology, but integrating these approaches may be essential for full insight into cellular-level mechanisms underlying brain function and dysfunction. Applying this approach to the habenula (a structure with diverse, intermingled molecular, anatomical, and computational features), we identified encoding of reward-predictive cues and reward outcomes in distinct genetically defined neural populations, including TH cells and Tac1 cells. Data from genetically targeted recordings were used to train an optimized nonlinear dynamical systems model and revealed activity dynamics consistent with a line attractor. High-density, cell-type-specific electrophysiological recordings and optogenetic perturbation provided supporting evidence for this model. Reverse-engineering predicted how Tac1 cells might integrate reward history, which was complemented by in vivo experimentation. This integrated approach describes a process by which data-driven computational models of population activity can generate and frame actionable hypotheses for cell-type-specific investigation in biological systems.
Topics: Habenula; Population Dynamics; Reward
PubMed: 36113428
DOI: 10.1016/j.cell.2022.08.019 -
Nature Reviews. Neuroscience Jul 2023The thalamus is a small, bilateral structure in the diencephalon that integrates signals from many areas of the CNS. This critical anatomical position allows the... (Review)
Review
The thalamus is a small, bilateral structure in the diencephalon that integrates signals from many areas of the CNS. This critical anatomical position allows the thalamus to influence whole-brain activity and adaptive behaviour. However, traditional research paradigms have struggled to attribute specific functions to the thalamus, and it has remained understudied in the human neuroimaging literature. Recent advances in analytical techniques and increased accessibility to large, high-quality data sets have brought forth a series of studies and findings that (re-)establish the thalamus as a core region of interest in human cognitive neuroscience, a field that otherwise remains cortico-centric. In this Perspective, we argue that using whole-brain neuroimaging approaches to investigate the thalamus and its interaction with the rest of the brain is key for understanding systems-level control of information processing. To this end, we highlight the role of the thalamus in shaping a range of functional signatures, including evoked activity, interregional connectivity, network topology and neuronal variability, both at rest and during the performance of cognitive tasks.
Topics: Humans; Magnetic Resonance Imaging; Brain; Cognition; Thalamus; Neuroimaging; Neural Pathways
PubMed: 37237103
DOI: 10.1038/s41583-023-00701-0 -
Nature Jun 2023In many species, including mice, female animals show markedly different pup-directed behaviours based on their reproductive state. Naive wild female mice often kill...
In many species, including mice, female animals show markedly different pup-directed behaviours based on their reproductive state. Naive wild female mice often kill pups, while lactating female mice are dedicated to pup caring. The neural mechanisms that mediate infanticide and its switch to maternal behaviours during motherhood remain unclear. Here, on the basis of the hypothesis that maternal and infanticidal behaviours are supported by distinct and competing neural circuits, we use the medial preoptic area (MPOA), a key site for maternal behaviours, as a starting point and identify three MPOA-connected brain regions that drive differential negative pup-directed behaviours. Functional manipulation and in vivo recording reveal that oestrogen receptor α (ESR1)-expressing cells in the principal nucleus of the bed nucleus of stria terminalis (BNSTpr) are necessary, sufficient and naturally activated during infanticide in female mice. MPOA and BNSTpr neurons form reciprocal inhibition to control the balance between positive and negative infant-directed behaviours. During motherhood, MPOA and BNSTpr cells change their excitability in opposite directions, supporting a marked switch of female behaviours towards the young.
Topics: Animals; Female; Mice; Infanticide; Lactation; Maternal Behavior; Neural Pathways; Preoptic Area; Thalamus
PubMed: 37286598
DOI: 10.1038/s41586-023-06147-9 -
Trends in Neurosciences Jul 2021Early anatomical evidence suggested that the paraventricular nucleus of the thalamus (PVT) regulates arousal, as well as emotional and motivated behaviors. We discuss... (Review)
Review
Early anatomical evidence suggested that the paraventricular nucleus of the thalamus (PVT) regulates arousal, as well as emotional and motivated behaviors. We discuss recent studies using modern techniques which now confirm and expand the involvement of the rodent PVT in these functions. Despite the emerging notion that the PVT is implicated in various behavioral processes, a recurrent theme is that activity in this brain region depends on internal state information arriving from the hypothalamus and brainstem, and is influenced by prior experience. We propose that the primary function of the PVT is to detect homeostatic challenges by integrating information about prior experiences, competing needs, and internal state to guide adaptive behavioral responses aimed at restoring homeostasis.
Topics: Homeostasis; Humans; Midline Thalamic Nuclei; Neurons; Paraventricular Hypothalamic Nucleus; Thalamus
PubMed: 33775435
DOI: 10.1016/j.tins.2021.03.001 -
Nature Sep 2023Oxytocin is a neuropeptide that is important for maternal physiology and childcare, including parturition and milk ejection during nursing. Suckling triggers the release...
Oxytocin is a neuropeptide that is important for maternal physiology and childcare, including parturition and milk ejection during nursing. Suckling triggers the release of oxytocin, but other sensory cues-specifically, infant cries-can increase the levels of oxytocin in new human mothers, which indicates that cries can activate hypothalamic oxytocin neurons. Here we describe a neural circuit that routes auditory information about infant vocalizations to mouse oxytocin neurons. We performed in vivo electrophysiological recordings and photometry from identified oxytocin neurons in awake maternal mice that were presented with pup calls. We found that oxytocin neurons responded to pup vocalizations, but not to pure tones, through input from the posterior intralaminar thalamus, and that repetitive thalamic stimulation induced lasting disinhibition of oxytocin neurons. This circuit gates central oxytocin release and maternal behaviour in response to calls, providing a mechanism for the integration of sensory cues from the offspring in maternal endocrine networks to ensure modulation of brain state for efficient parenting.
Topics: Animals; Female; Mice; Cues; Hypothalamus; Maternal Behavior; Neural Pathways; Neurons; Oxytocin; Photometry; Thalamic Nuclei; Vocalization, Animal; Wakefulness
PubMed: 37730989
DOI: 10.1038/s41586-023-06540-4 -
Nature Neuroscience Jul 2023Excitatory projections from the lateral hypothalamic area (LHA) to the lateral habenula (LHb) drive aversive responses. We used patch-sequencing (Patch-seq) guided...
Excitatory projections from the lateral hypothalamic area (LHA) to the lateral habenula (LHb) drive aversive responses. We used patch-sequencing (Patch-seq) guided multimodal classification to define the structural and functional heterogeneity of the LHA-LHb pathway. Our classification identified six glutamatergic neuron types with unique electrophysiological properties, molecular profiles and projection patterns. We found that genetically defined LHA-LHb neurons signal distinct aspects of emotional or naturalistic behaviors, such as estrogen receptor 1-expressing (Esr1) LHA-LHb neurons induce aversion, whereas neuropeptide Y-expressing (Npy) LHA-LHb neurons control rearing behavior. Repeated optogenetic drive of Esr1 LHA-LHb neurons induces a behaviorally persistent aversive state, and large-scale recordings showed a region-specific neural representation of the aversive signals in the prelimbic region of the prefrontal cortex. We further found that exposure to unpredictable mild shocks induced a sex-specific sensitivity to develop a stress state in female mice, which was associated with a specific shift in the intrinsic properties of bursting-type Esr1 LHA-LHb neurons. In summary, we describe the diversity of LHA-LHb neuron types and provide evidence for the role of Esr1 neurons in aversion and sexually dimorphic stress sensitivity.
Topics: Female; Mice; Animals; Habenula; Hypothalamus; Hypothalamic Area, Lateral; Neurons; Affect; Neural Pathways
PubMed: 37349481
DOI: 10.1038/s41593-023-01367-8 -
Neuron Apr 2022Chronic stress is a major risk factor for depression onset. However, it remains unclear how repeated stress sculpts neural circuits and finally elicits depression. Given...
Chronic stress is a major risk factor for depression onset. However, it remains unclear how repeated stress sculpts neural circuits and finally elicits depression. Given the essential role of lateral habenula (LHb) in depression, here, we attempt to clarify how LHb-centric neural circuitry integrates stress-related information. We identify lateral hypothalamus (LH) as the most physiologically relevant input to LHb under stress. LH neurons fire with a unique pattern that efficiently drives postsynaptic potential summation and a closely followed LHb bursting (EPSP-burst pairing) in response to various stressors. We found that LH-LHb synaptic potentiation is determinant in stress-induced depression. Mimicking this repeated EPSP-burst pairings at LH-LHb synapses by photostimulation, we artificially induced an "emotional status" merely by potentiating this pathway in mice. Collectively, these results delineate the spatiotemporal dynamics of chronic stress processing from forebrain onto LHb in a pathway-, cell-type-, and pattern-specific manner, shedding light on early interventions before depression onset.
Topics: Animals; Depression; Habenula; Hypothalamic Area, Lateral; Hypothalamus; Mice; Synapses
PubMed: 35114101
DOI: 10.1016/j.neuron.2022.01.011 -
Nature Mar 2022Most social species self-organize into dominance hierarchies, which decreases aggression and conserves energy, but it is not clear how individuals know their social...
Most social species self-organize into dominance hierarchies, which decreases aggression and conserves energy, but it is not clear how individuals know their social rank. We have only begun to learn how the brain represents social rank and guides behaviour on the basis of this representation. The medial prefrontal cortex (mPFC) is involved in social dominance in rodents and humans. Yet, precisely how the mPFC encodes relative social rank and which circuits mediate this computation is not known. We developed a social competition assay in which mice compete for rewards, as well as a computer vision tool (AlphaTracker) to track multiple, unmarked animals. A hidden Markov model combined with generalized linear models was able to decode social competition behaviour from mPFC ensemble activity. Population dynamics in the mPFC predicted social rank and competitive success. Finally, we demonstrate that mPFC cells that project to the lateral hypothalamus promote dominance behaviour during reward competition. Thus, we reveal a cortico-hypothalamic circuit by which the mPFC exerts top-down modulation of social dominance.
Topics: Animals; Hypothalamic Area, Lateral; Hypothalamus; Mice; Prefrontal Cortex; Reward; Social Behavior
PubMed: 35296862
DOI: 10.1038/s41586-022-04507-5