Explore the vast range of titles available.

The hippocampus is essential for spatial and episodic memory but is damaged early in Alzheimer’s disease and is very sensitive to hypoxia. Understanding how it regulates its oxygen supply is therefore key for designing interventions to preserve its function. However, studies of neurovascular function in the hippocampus in vivo have been limited by its relative inaccessibility. Here we compared hippocampal and visual cortical neurovascular function in awake mice, using two photon imaging of individual neurons and vessels and measures of regional blood flow and haemoglobin oxygenation. We show that blood flow, blood oxygenation and neurovascular coupling were decreased in the hippocampus compared to neocortex, because of differences in both the vascular network and pericyte and endothelial cell function. Modelling oxygen diffusion indicates that these features of the hippocampal vasculature may restrict oxygen availability and could explain its sensitivity to damage during neurological conditions, including Alzheimer’s disease, where the brain’s energy supply is decreased. The hippocampus is particularly sensitive to hypoxia but it has been difficult to study blood flow in this region. Here the authors compare the neurovascular function of the hippocampus and cortex and in awake mice, and find differences associated with microvascular structure.

Injury to the central nervous system (CNS) alters the molecular and cellular composition of neural tissue and leads to glial scarring, which inhibits the regrowth of damaged axons. Mammalian glial scars supposedly form a chemical and mechanical barrier to neuronal regeneration. While tremendous effort has been devoted to identifying molecular characteristics of the scar, very little is known about its mechanical properties. Here we characterize spatiotemporal changes of the elastic stiffness of the injured rat neocortex and spinal cord at 1.5 and three weeks post-injury using atomic force microscopy. In contrast to scars in other mammalian tissues, CNS tissue significantly softens after injury. Expression levels of glial intermediate filaments (GFAP, vimentin) and extracellular matrix components (laminin, collagen IV) correlate with tissue softening. As tissue stiffness is a regulator of neuronal growth, our results may help to understand why mammalian neurons do not regenerate after injury. Glial scars are thought to provide a biochemical and mechanical barrier to neuronal regeneration post-injury, but the mechanical properties of the scars have not been studied in detail. Here the authors perform atomic force microscopy measurements of glial scars from the injured rat cortex and spinal cord, and find that brain tissue softens in response to the injury.

Hattori et al . review the recent advances in our understanding of the roles of inhibitory neuron subtypes in shaping the activity and plasticity states of neocortical circuits, how neuromodulators control inhibitory neuron subtypes, and the role of inhibitory neuron dysfunction in neurological disorders. Neocortical inhibitory neurons exhibit remarkably diverse morphology, physiological properties and connectivity. Genetic access to molecularly defined subtypes of inhibitory neurons has aided their functional characterization in recent years. These studies have established that, instead of simply balancing excitatory neuron activity, inhibitory neurons actively shape excitatory circuits in a subtype-specific manner. We review the emerging view that inhibitory neuron subtypes perform context-dependent modulation of excitatory activity, as well as regulate experience-dependent plasticity of excitatory circuits. We then review the roles of neuromodulators in regulating the subtype-specific functions of inhibitory neurons. Finally, we discuss the idea that dysfunctions of inhibitory neuron subtypes may be responsible for various aspects of neurological disorders.

The sensory, associative and limbic neocortical structures play a critical role in shaping incoming noxious inputs to generate variable pain perceptions. Technological advances in tracing circuitry and interrogation of pathways and complex behaviours are now yielding critical knowledge of neocortical circuits, cellular contributions and causal relationships between pain perception and its abnormalities in chronic pain. Emerging insights into neocortical pain processing suggest the existence of neocortical causality and specificity for pain at the level of subdomains, circuits and cellular entities and the activity patterns they encode. These mechanisms provide opportunities for therapeutic intervention for improved pain management.Neocortical circuits imparting specificity and causality to pain are not well understood. In this Review, Kuner and Tan discuss new insights into the contributions of diverse cerebral domains, their connectivity and their plasticity to the sensory and emotional aspects of pain.

The epileptic network is characterized by pathologic, seizure-generating 'foci' embedded in a web of structural and functional connections. Clinically, seizure foci are considered optimal targets for surgery. However, poor surgical outcome suggests a complex relationship between foci and the surrounding network that drives seizure dynamics. We developed a novel technique to objectively track seizure states from dynamic functional networks constructed from intracranial recordings. Each dynamical state captures unique patterns of network connections that indicate synchronized and desynchronized hubs of neural populations. Our approach suggests that seizures are generated when synchronous relationships near foci work in tandem with rapidly changing desynchronous relationships from the surrounding epileptic network. As seizures progress, topographical and geometrical changes in network connectivity strengthen and tighten synchronous connectivity near foci-a mechanism that may aid seizure termination. Collectively, our observations implicate distributed cortical structures in seizure generation, propagation and termination, and may have practical significance in determining which circuits to modulate with implantable devices.

Balance of excitation and inhibition is a fundamental feature of in vivo network activity and is important for its computations. However, its presence in the neocortex of higher mammals is not well established. We investigated the dynamics of excitation and inhibition using dense multielectrode recordings in humans and monkeys. We found that in all states of the wake-sleep cycle, excitatory and inhibitory ensembles are well balanced and co-fluctuate with slight instantaneous deviations from perfect balance, mostly in slow-wave sleep. Remarkably, these correlated fluctuations are seen for many different temporal scales. The similarity of these computational features with a network model of self-generated balanced states suggests that such balanced activity is essentially generated by recurrent activity in the local network and is not due to external inputs. Finally, we find that this balance breaks down during seizures, where the temporal correlation of excitatory and inhibitory populations is disrupted. These results show that balanced activity is a feature of normal brain activity and break down of the balance could be an important factor to define pathological states.

Despite decades of research, we still do not understand how spontaneous human seizures start and spread – especially at the level of neuronal microcircuits. In this study, we used laminar arrays of micro-electrodes to simultaneously record the local field potentials and multi-unit neural activities across the six layers of the neocortex during focal seizures in humans. We found that, within the ictal onset zone, the discharges generated during a seizure consisted of current sinks and sources only within the infra-granular and granular layers. Outside of the seizure onset zone, ictal discharges reflected current flow in the supra-granular layers. Interestingly, these patterns of current flow evolved during the course of the seizure – especially outside the seizure onset zone where superficial sinks and sources extended into the deeper layers. Based on these observations, a framework describing cortical-cortical dynamics of seizures is proposed with implications for seizure localization, surgical targeting, and neuromodulation techniques to block the generation and propagation of seizures. How seizure propagation occurs across cortical layers in humans is not fully understood. Here the authors use intracerebral laminar electrodes (capable of recording the six layers of the cortex) during pre-surgical evaluations, and identify a signature of the area responsible for seizures characterized by pathological activities in the granular and infragranular layers.

Surgery is widely accepted as an effective therapy for selected individuals with medically refractory epilepsy. Numerous studies in the past 20 years have reported seizure freedom for at least 1 year in 53–84% of patients after anteromesial temporal lobe resections for mesial temporal lobe sclerosis, in 66–100% of patients with dual pathology, in 36–76% of patients with localised neocortical epilepsy, and in 43–79% of patients after hemispherectomies. Reported rates for non-resective surgery have been less impressive in terms of seizure freedom; however, the benefit is more apparent when reported in terms of significant seizure reductions. In this Review, we consider the outcomes of surgery in adults and children with epilepsy and review studies of neurological and cognitive sequelae, psychiatric and behavioural outcomes, and overall health-related quality of life.

Abstract Alterations in neocortical GABAergic interneurons (INs) have been affiliated with neuropsychiatric diseases, including schizophrenia (SZ). Significant progress has been made linking the function of a specific subtype of GABAergic cells, parvalbumin (PV) positive INs, to altered gamma-band oscillations, which, in turn, underlie perceptual and feedforward information processing in cortical circuits. Here, we review a smaller but growing volume of literature focusing on a separate subtype of neocortical GABAergic INs, somatostatin (SST) positive INs. Despite sharing similar neurodevelopmental origins, SSTs exhibit distinct morphology and physiology from PVs. Like PVs, SSTs are altered in postmortem brain samples from multiple neocortical regions in SZ, although basic and translational research into consequences of SST dysfunction has been relatively sparse. We highlight a growing body of work in rodents, which now indicates that SSTs may also underlie specific aspects of cortical circuit function, namely low-frequency oscillations, disinhibition, and mediation of cortico-cortical feedback. SSTs may thereby support the coordination of local cortical information processing with more global spatial, temporal, and behavioral context, including predictive coding and working memory. These functions are notably deficient in some cases of SZ, as well as other neuropsychiatric disorders, emphasizing the importance of focusing on SSTs in future translational studies. Finally, we highlight the challenges that remain, including subtypes within the SST class.

Focal cortical dysplasia (FCD) is a leading cause of drug-resistant epilepsy; however, the mechanisms underlying hyperexcitability in the affected cortical regions remain poorly understood. In this study, we employed a freeze-induced neocortical malformation model in rats to investigate the electrophysiological properties of pyramidal neurons surrounding the microgyrus and to evaluate changes in synaptic transmission. Using whole-cell patch-clamp recordings, we analyzed passive and active membrane properties, synaptic responses, and epileptiform activity in brain slices from rats with FCD and sham-operated controls. Our results revealed that while the intrinsic biophysical properties of neurons remained largely unchanged, the summation of excitatory and inhibitory inputs was significantly enhanced. Notably, the balance of inhibitory and excitatory synaptic currents was shifted toward excitation, making the perilesional cortex more susceptible to seizure generation. In a model of epileptiform activity induced by GABAA receptor blockade and reduced Mg2+ concentration, we observed early ictal activity originating in the microgyrus and spreading to adjacent regions. These findings demonstrate that synaptic perturbations, rather than alterations in intrinsic neuronal properties, are the primary drivers of hyperexcitability in this model. Our study highlights the importance of synaptic dysregulation in FCD-related epilepsy and suggests that targeting synaptic transmission may offer a promising therapeutic strategy for controlling seizures in patients with cortical malformations.