Within the first few days of life, humans are colonized by commensal intestinal microbiota. Here, we review recent findings showing that microbiota are important in normal healthy brain function. We also discuss the relation between stress and microbiota, and how alterations in microbiota influence stress-related behaviors. New studies show that bacteria, including commensal, probiotic, and pathogenic bacteria, in the gastrointestinal (GI) tract can activate neural pathways and central nervous system (CNS) signaling systems. Ongoing and future animal and clinical studies aimed at understanding the microbiota–gut–brain axis may provide novel approaches for prevention and treatment of mental illness, including anxiety and depression.
Within the first few days of life, humans are colonized by commensal intestinal microbiota. Here, we review recent findings showing that microbiota are important in normal healthy brain function. We also discuss the relation between stress and microbiota, and how alterations in microbiota influence stress-related behaviors. New studies show that bacteria, including commensal, probiotic, and pathogenic bacteria, in the gastrointestinal (GI) tract can activate neural pathways and central nervous system (CNS) signaling systems. Ongoing and future animal and clinical studies aimed at understanding the microbiota-gut-brain axis may provide novel approaches for prevention and treatment of mental illness, including anxiety and depression.
Highlights • Photoreceptive retinal ganglion cells (ipRGCs) regulate behavior and physiology. • ipRGCs use melanopsin-dependent intrinsic light responses and rod/cone inputs. • The relative contribution of each photoreceptor to evoked responses is not fully understood. • A method for quantifying light is presented that accounts for complex photoreceptive inputs. • Guidance for those designing architectural and therapeutic lighting is provided.
Oxytocin and vasopressin are regulators of anxiety, stress-coping, and sociality. They are released within hypothalamic and limbic areas from dendrites, axons, and perikarya independently of, or coordinated with, secretion from neurohypophysial terminals. Central oxytocin exerts anxiolytic and antidepressive effects, whereas vasopressin tends to show anxiogenic and depressive actions. Evidence from pharmacological and genetic association studies confirms their involvement in individual variation of emotional traits extending to psychopathology. Based on their opposing effects on emotional behaviors, we propose that a balanced activity of both brain neuropeptide systems is important for appropriate emotional behaviors. Shifting the balance between the neuropeptide systems towards oxytocin, by positive social stimuli and/or psychopharmacotherapy, may help to improve emotional behaviors and reinstate mental health.
Deficits in cognitive control, a core disturbance of schizophrenia, appear to emerge from impaired prefrontal gamma oscillations. Cortical gamma oscillations require strong inhibitory inputs to pyramidal neurons from the parvalbumin basket cell (PVBC) class of GABAergic neurons. Recent findings indicate that schizophrenia is associated with multiple pre- and postsynaptic abnormalities in PVBCs, each of which weakens their inhibitory control of pyramidal cells. These findings suggest a new model of cortical dysfunction in schizophrenia in which PVBC inhibition is decreased to compensate for an upstream deficit in pyramidal cell excitation. This compensation is thought to rebalance cortical excitation and inhibition, but at a level insufficient to generate the gamma oscillation power required for high levels of cognitive control.
Highlights • We provide a comprehensive overview of the role of glucose metabolism in normal brain function. • We analyze the contribution of glucose metabolism to brain physiology. • We discuss controversies in energy substrate consumption and utilization. • We highlight the connection between glucose metabolism and cell death. • We review the pathophysiological consequences of balanced and disturbed glucose metabolism.
Reactive astrogliosis, whereby astrocytes undergo varying molecular and morphological changes, is a ubiquitous but poorly understood hallmark of all central nervous system pathologies. Genetic tools are now enabling the molecular dissection of the functions and mechanisms of reactive astrogliosis in vivo . Recent studies provide compelling evidence that reactive astrogliosis can exert both beneficial and detrimental effects in a context-dependent manner determined by specific molecular signaling cascades. Reactive astrocytes can have both loss of normal functions and gain of abnormal effects that could feature prominently in a variety of disease processes. This article reviews developments in the signaling mechanisms that regulate specific aspects of reactive astrogliosis and highlights the potential to identify novel therapeutic molecular targets for diverse neurological disorders.
Epilepsy is characterized by recurrent spontaneous seizures due to hyperexcitability and hypersynchrony of brain neurons. Current theories of pathophysiology stress neuronal dysfunction and damage, and aberrant connections as relevant factors. Most antiepileptic drugs target neuronal mechanisms. However, nearly one-third of patients have seizures that are refractory to available medications; a deeper understanding of mechanisms may be required to conceive more effective therapies. Recent studies point to a significant contribution by non-neuronal cells, the glia – especially astrocytes and microglia – in the pathophysiology of epilepsy. This review critically evaluates the role of glia-induced hyperexcitability and inflammation in epilepsy.
The ability to discriminate among similar experiences is a crucial feature of episodic memory. This ability has long been hypothesized to require the hippocampus, and computational models suggest that it is dependent on pattern separation. However, empirical data for the role of the hippocampus in pattern separation have not been available until recently. This review summarizes data from electrophysiological recordings, lesion studies, immediate-early gene imaging, transgenic mouse models, as well as human functional neuroimaging, that provide convergent evidence for the involvement of particular hippocampal subfields in this key process. We discuss the impact of aging and adult neurogenesis on pattern separation, and also highlight several challenges to linking across species and approaches, and suggest future directions for investigation.
Stress initiates an intricate response that affects diverse cognitive and affective domains, with the goal of improving survival chances in the light of changing environmental challenges. Here, we bridge animal data at cellular and systems levels with human work on brain-wide networks to propose a framework describing how stress-related neuromodulators trigger dynamic shifts in network balance, enabling an organism to comprehensively reallocate its neural resources according to cognitive demands. We argue that exposure to acute stress prompts a reallocation of resources to a salience network, promoting fear and vigilance, at the cost of an executive control network. After stress subsides, resource allocation to these two networks reverses, which normalizes emotional reactivity and enhances higher-order cognitive processes important for long-term survival.
Highlights • Exome sequencing has identified rare mutations and novel genes in ASD and ID cases. • Targeted resequencing has confirmed association for several novel genes. • Results from exome sequencing of 1058 families suggests a convergence of functional pathways. • We review genetic and neurobiological evidence for chromatin, wnt, and synaptic function pathways.
Despite decades of intensive research, the biological mechanisms that causally underlie depression are still unclear, and therefore the development of novel effective antidepressant treatments is hindered. Recent studies indicate that impairment of the normal structure and function of microglia, caused by either intense inflammatory activation (e.g., following infections, trauma, stroke, short-term stress, autoimmune or neurodegenerative diseases) or by decline and senescence of these cells (e.g., during aging, Alzheimer's disease, or chronic unpredictable stress exposure), can lead to depression and associated impairments in neuroplasticity and neurogenesis. Accordingly, some forms of depression can be considered as a microglial disease (microgliopathy), which should be treated by a personalized medical approach using microglial inhibitors or stimulators depending on the microglial status of the depressed patient.
Anhedonia, or markedly diminished interest or pleasure, is a hallmark symptom of major depression, schizophrenia and other neuropsychiatric disorders. Over the past three decades, the clinical definition of anhedonia has remained relatively unchanged, although cognitive psychology and behavioral neuroscience have expanded our understanding of other reward-related processes. Here, we review the neural bases of the construct of anhedonia that reflects deficits in hedonic capacity and also closely linked to the constructs of reward valuation, decision-making, anticipation and motivation. The neural circuits subserving these reward-related processes include the ventral striatum, prefrontal cortical regions, and afferent and efferent projections. An understanding of anhedonia and other reward-related constructs will facilitate the diagnosis and treatment of disorders that include reward deficits as key symptoms.
Highlights • The zebrafish is a popular novel model in translational neuroscience research. • Both larval and adult zebrafish contribute to modeling complex brain disorders. • Zebrafish models can be used to study CNS cancer, epilepsy, anxiety, and autism. • Zebrafish are highly sensitive to major classes of neurotropic drugs. • Zebrafish are a useful tool for high-throughput genetic and small molecule screening.
The term ‘tripartite synapse’ refers to a concept in synaptic physiology based on the demonstration of the existence of bidirectional communication between astrocytes and neurons. Consistent with this concept, in addition to the classic ‘bipartite’ information flow between the pre- and postsynaptic neurons, astrocytes exchange information with the synaptic neuronal elements, responding to synaptic activity and, in turn, regulating synaptic transmission. Because recent evidence has demonstrated that astrocytes integrate and process synaptic information and control synaptic transmission and plasticity, astrocytes, being active partners in synaptic function, are cellular elements involved in the processing, transfer and storage of information by the nervous system. Consequently, in contrast to the classically accepted paradigm that brain function results exclusively from neuronal activity, there is an emerging view, which we review herein, in which brain function actually arises from the coordinated activity of a network comprising both neurons and glia.
Mammalian target of rapamycin (mTOR) is a protein kinase involved in translation control and long-lasting synaptic plasticity. mTOR functions as the central component of two multi-protein signaling complexes, mTORC1 and mTORC2, which can be distinguished from each other based on their unique compositions and substrates. Although the majority of evidence linking mTOR function to synaptic plasticity comes from studies utilizing rapamycin, studies in genetically modified mice also suggest that mTOR couples receptors to the translation machinery for establishing long-lasting synaptic changes that are the basis for higher order brain function, including long-term memory. Finally, perturbation of the mTOR signaling cascade appears to be a common pathophysiological feature of human neurological disorders, including mental retardation syndromes and autism spectrum disorders.
Highlights • tDCS can modulate membrane potentials, synaptic processes, and functional networks. • Neural oscillations can be modified by tDCS, affecting perception and cognition. • Different tDCS protocols can enhance or disrupt attention, learning, and memory. • Variability in polarity-specific modulations may reflect neural coding properties. • tDCS is complementary to, and can be used in parallel with, methods such as TMS.
Highlights • GFAP is tightly regulated at mRNA level and by PTMs. • GFAP plays a critical role in astrogliosis after CNS injury and in neurodegeneration. • GFAP is a potential drug target for Alexander's disease and neurodegeneration. • GFAP and GFAP-BDPs are emerging biomarkers for TBI and neuroinjuries.
Highlights • Parkinson's disease is a mitochondrial disease of aging. • PINK1 and parkin are key players in multiple domains of mitochondrial health. • PINK1 and parkin are key regulators of mitochondrial quality control.
A basic feature of intelligent systems such as the cerebral cortex is the ability to freely associate aspects of perceived experience with an internal representation of the world and make predictions about the future. Here, a hypothesis is presented that the extraordinary performance of the cortex derives from an associative mechanism built in at the cellular level to the basic cortical neuronal unit: the pyramidal cell. The mechanism is robustly triggered by coincident input to opposite poles of the neuron, is exquisitely matched to the large- and fine-scale architecture of the cortex, and is tightly controlled by local microcircuits of inhibitory neurons targeting subcellular compartments. This article explores the experimental evidence and the implications for how the cortex operates.