Most animals live under constant threat from predators, and predation has been a major selective force inshaping animal behaviour. Nevertheless, defence responses against predatory threats need to be balanced against other adaptive behaviours such as foraging, mating and recovering from infection. This behavioural balance in ethologically relevant contexts requires adequate integration of internal and external signals in a complex interplay between the brain and the body. Despite this complexity, research has often considered defensive behaviour as entirely mediated by the brain processing threat-related information obtained via perception of the external environment. However, accumulating evidence suggests that theendocrine, immune, gastrointestinal and reproductive systems have important roles in modulating behavioural responses to threat. In this Review, we focus on how predatory threat defence responses are shaped by threat imminence and review the circuitry between subcortical brain regions involved in mediating defensive behaviours. Then, we discuss the intersection of peripheral systems involved in internal states related to infection, hunger and mating with the neurocircuits that underlie defence responses against predatory threat. Through this process, we aim to elucidate the interconnections between the brain and body as an integrated network that facilitates appropriate defensive responses to threat and todiscuss the implications for future behavioural research.

When linguistic dogma rejects a neuroscientific hypothesis K

Neuronal membrane excitability must be resilient to perturbations that can take place over timescales from milliseconds to months (or even years in long-lived animals). A great deal of attention has been paid to classes of homeostatic mechanisms that contribute to long-term maintenance of neuronal excitability through processes that alter a key structural parameter: the number of ion channel proteins present at the neuronal membrane. However, less attention has been paid to the self-regulating 'automatic' mechanisms that contribute to neuronal resilience by virtue of the kinetic properties of ion channels themselves. Here, we propose that these two sets of mechanisms are complementary instantiations of feedback control, together enabling resilience on a wide range of temporal scales. We further point to several methodological and conceptual challenges entailed in studying these processes - both of which involve enmeshed feedback control loops - and consider the consequences of these mechanisms of resilience.

Neurodegenerative diseases are the most common cause of dementia. Although their underlying molecular pathologies have been identified, there is substantial heterogeneity in the patterns of progressive brain alterations across and within these diseases. Recent advances in neuroimaging methods have revealed that pathological proteins accumulate along specific macroscale brain networks, implicating the network architecture of the brain in the system-level pathophysiology of neurodegenerative diseases. However, the extent to which 'network-based neurodegeneration' applies across the wide range of neurodegenerative disorders remains unclear. Here, we discuss the state-of-the-art of neuroimaging-based connectomics for the mapping and prediction of neurodegenerative processes. We review findings supporting brain networks as passive conduits through which pathological proteins spread. As an alternative view, we also discuss complementary work suggesting that network alterations actively modulate the spreading of pathological proteins between connected brain regions. We conclude this Perspective by proposing an integrative framework in which connectome-based models can be advanced along three dimensions of innovation: incorporating parameters that modulate propagation behaviour on the basis of measurable biological features; building patient-tailored models that use individual-level information and allowing model parameters to interact dynamically over time. We discuss promises and pitfalls of these strategies for improving disease insights and moving towards precision medicine.

Extracellular vesicles (EVs) have recently emerged as versatile elements of cell communication in the nervous system, mediating tissue homeostasis. EVs influence the physiology of their target cellsvia horizontal transfer of molecular cargo between cells and by triggering signalling pathways. In this Review, we discuss recent work revealing that EVs mediate interactions between oligodendrocytes and neurons, which are relevant for maintaining the structural integrity of axons. In response to neuronal activity, myelinating oligodendrocytes release EVs, which are internalized by neurons and provide axons with key factors that improve axonal transport, stress resistance and energy homeostasis. Glia-to-neuron transfer of EVs is thus a crucial facet of axonal preservation. When glial support is impaired, axonal integrity is progressively lost, as observed in myelin-related disorders, other neurodegenerative diseases and with normal ageing. We highlight the mechanisms that oligodendroglial EVs use to sustain axonal integrity and function.

Acetylcholine plays an essential role in fundamental aspects of cognition. Studies that have mapped the activity and functional connectivity of cholinergic neurons have shown that the axons of basal forebrain cholinergic neurons innervate the pallium with far more topographical and functional organization than was historically appreciated. Together with the results of studies using new probes that allow release of acetylcholine to be detected with high spatial and temporal resolution, these findings have implicated cholinergic networks in 'binding' diverse behaviours that contribute to cognition. Here, we review recent findings on the developmental origins, connectivity and function of cholinergic neurons, and explore the participation of cholinergic signalling in the encoding of cognition-related behaviours.

The hypothalamus is an evolutionarily conserved endocrine interface that, among other roles, links central homeostatic control to adaptive bodily responses by releasing hormones and neuropeptides from its many neuronal subtypes. In its preoptic, anterior, tuberal and mammillary subdivisions, a kaleidoscope of magnocellular and parvocellular neuroendocrine command neurons, local-circuit neurons, and neurons that project to extrahypothalamic areas are intermingled in partially overlapping patches of nuclei. Molecular fingerprinting has produced data of unprecedented mass and depth to distinguish and even to predict the synaptic and endocrine competences, connectivity and stimulus selectivity of many neuronal modalities. These new insights support eminent studies from the past century but challenge others on the molecular rules that shape the developmental segregation of hypothalamic neuronal subtypes and their use of morphogenic cues for terminal differentiation. Here, we integrate single-cell RNA sequencing studies with those of mouse genetics and endocrinology to describe key stages of hypothalamus development, including local neurogenesis, the direct terminal differentiation of glutamatergic neurons, transition cascades for GABAergic and GABAergic cell-derived dopamine cells, waves of local neuronal migration, and sequential enrichment in neuropeptides and hormones. We particularly emphasize how transcription factors determine neuronal identity and, consequently, circuit architecture, and whether their deviations triggered by environmental factors and hormones provoke neuroendocrine illnesses.

GABAergic inhibitory circuits play an essential role in coordinating various hippocampal functions. Several decades of work dedicated to a thorough characterization of hippocampal inhibitory populations have highlighted how specific types of interneuron can contribute to network activity. Recent studies have used genetically targeted recordings and peturbations of activity during memory-related behaviours to determine how interneurons that inhibit distinct subcellular domains of principal cells or specialize in principal cell disinhibition may sculpt hippocampal memory. These studies highlight unique contributions of distinct interneuron types to the temporal binding of hippocampal ensembles, synaptic plasticity and the acquisition of spatial and contextual information. Here, we review the current state of knowledge around hippocampal inhibition and memory by discussing the multifaceted roles of populations of inhibitory cells at different stages of hippocampal mnemonic processing.