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The lateral parabrachial nucleus (LPBN) is known to relay noxious information to the amygdala for processing affective responses. However, it is unclear whether the LPBN actively processes neuropathic pain characterized by persistent hyperalgesia with aversive emotional responses. Here we report that neuropathic pain-like hypersensitivity induced by common peroneal nerve (CPN) ligation increases nociceptive stimulation-induced responses in glutamatergic LPBN neurons. Optogenetic activation of GABAergic LPBN neurons does not affect basal nociception, but alleviates neuropathic pain-like behavior. Optogenetic activation of glutamatergic or inhibition of GABAergic LPBN neurons induces neuropathic pain-like behavior in naïve mice. Inhibition of glutamatergic LPBN neurons alleviates both basal nociception and neuropathic pain-like hypersensitivity. Repetitive pharmacogenetic activation of glutamatergic or GABAergic LPBN neurons respectively mimics or prevents the development of CPN ligation-induced neuropathic pain-like hypersensitivity. These findings indicate that a delicate balance between excitatory and inhibitory LPBN neuronal activity governs the development and maintenance of neuropathic pain. The parabrachial nucleus (PBN) projects to the amygdala, and contributes to affective aspects of neuropathic pain. Here the authors demonstrate that the lateral parabrachial nucleus (LPBN) contributes to hypersensitivity in a mouse model of neuropathic pain.

Autism spectrum disorder (ASD) is thought to emerge during early cortical development. However, the exact developmental stages and associated molecular networks that prime disease propensity are elusive. To profile early neurodevelopmental alterations in ASD with macrocephaly, we monitored subject-derived induced pluripotent stem cells (iPSCs) throughout the recapitulation of cortical development. Our analysis revealed ASD-associated changes in the maturational sequence of early neuron development, involving temporal dysregulation of specific gene networks and morphological growth acceleration. The observed changes tracked back to a pathologically primed stage in neural stem cells (NSCs), reflected by altered chromatin accessibility. Concerted over-representation of network factors in control NSCs was sufficient to trigger ASD-like features, and circumventing the NSC stage by direct conversion of ASD iPSCs into induced neurons abolished ASD-associated phenotypes. Our findings identify heterochronic dynamics of a gene network that, while established earlier in development, contributes to subsequent neurodevelopmental aberrations in ASD.

Synaptic pruning during adolescence is important for appropriate neurodevelopment and synaptic plasticity. Aberrant synaptic pruning may underlie a variety of brain disorders such as schizophrenia, autism and anxiety. Dopamine D2 receptor (Drd2) is associated with several neuropsychiatric diseases and is the target of some antipsychotic drugs. Here we generate self-reporting Drd2 heterozygous (SR-Drd2 +/− ) rats to simultaneously visualize Drd2-positive neurons and downregulate Drd2 expression. Time course studies on the developing anterior cingulate cortex (ACC) from control and SR-Drd2 +/− rats reveal important roles of Drd2 in regulating synaptic pruning rather than synapse formation. Drd2 also regulates LTD, a form of synaptic plasticity which includes some similar cellular/biochemical processes as synaptic pruning. We further demonstrate that Drd2 regulates synaptic pruning via cell-autonomous mechanisms involving activation of mTOR signaling. Deficits of Drd2-mediated synaptic pruning in the ACC during adolescence lead to hyper-glutamatergic function and anxiety-like behaviors in adulthood. Taken together, our results demonstrate important roles of Drd2 in cortical synaptic pruning. Synaptic pruning is important during development and synaptic plasticity. Here, the authors show that the dopamine D2 receptor (Drd2) in the anterior cingulate cortex regulates synaptic pruning, affecting LTD and behaviour in transgenic rats.

Development of the next generation of bio- and nano-electronics is inseparably connected to the innovative concept of emulation and reproduction of biological sensorimotor systems and artificial neurobotics. Here, we report for the first time principally new artificial bioinspired optoelectronic sensorimotor system for the controlable immitation of opto-genetically engineered neurons in the biological motor system. The device is based on inorganic optical synapse (In-doped TiO 2 nanofilm) assembled into a liquid metal (galinstan) actuator. The optoelectronic synapse generates polarised excitatory and inhibitory postsynaptic potentials to trigger the liquid metal droplet to vibrate and then mimic the expansion and contraction of biological fibre muscle. The low-energy consumption and precise modulation of electrical and mechanical outputs are the distinguished characteristics of fabricated sensorimotor system. This work is the underlying significant step towards the development of next generation of low-energy the internet of things for bioinspired neurorobotic and bioelectronic system. The internet of things technologies relies on the development of sensorimotor systems. Here, Karbalaei Akbari and Zhuiykov show a bioinspired sensorimotor system based on an integration of an artificial optical synapse and a liquid metal actuator, which mimics the expansion and contraction of biological muscles.

Major depressive disorder (MDD) is associated with reduced concentrations of γ-aminobutyric acid (GABA) that are normalized by antidepressant therapies. Moreover, depressive-like phenotypes of GABA A receptor mutant mice can be reversed by treatment with conventional antidepressants drugs, as well as by subanesthetic doses of ketamine. Thus GABAergic deficits may causally contribute to depressive disorders, while antidepressant therapies may enhance GABAergic synaptic transmission. Here we tested the hypothesis that sustained enhancement of GABAergic transmission alone is sufficient to elicit antidepressant-like behavior, using disinhibition of GABAergic interneurons. We focused on somatostatin-positive (SST + ) GABAergic interneurons because of evidence that their function is compromised in MDD. To disinhibit SST + interneurons, we inactivated the γ2 subunit gene of GABA A receptors selectively in these neurons (SSTCre:γ2 f/f mice). Loss of inhibitory synaptic input resulted in increased excitability of SST + interneurons. In turn, pyramidal cell targets of SST + neurons showed an increased frequency of spontaneous inhibitory postsynaptic currents. The behavior of SSTCre:γ2 f/f mice mimicked the effects of anxiolytic and antidepressant drugs in a number of behavioral tests, without affecting performance in a spatial learning- and memory-dependent task. Finally, brain extracts of SSTCre:γ2 f/f mice showed decreased phosphorylation of the eukaryotic elongation factor eEF2, reminiscent of the effects of ketamine. Importantly, these effects occurred without altered activity of the mammalian target of rapamycin pathway nor did they involve altered expression of SST. However, they were associated with reduced Ca 2+ /calmodulin-dependent auto-phosphorylation of eEF2 kinase, which controls the activity of eEF2 as its single target. Thus enhancing GABAergic inhibitory synaptic inputs from SST + interneurons to pyramidal cells and corresponding chronic reductions in the synaptic excitation:inhibition ratio represents a novel strategy for antidepressant therapies that reproduces behavioral and biochemical end points of rapidly acting antidepressants.

Prediabetes and Alzheimer’s disease both increase in prevalence with age. The former is a risk factor for the latter, but a mechanistic linkage between them remains elusive. We show that prediabetic serum hyperinsulinemia is reflected in the cerebrospinal fluid and that this chronically elevated insulin renders neurons resistant to insulin. This leads to abnormal electrophysiological activity and other defects. In addition, neuronal insulin resistance reduces hexokinase 2, thus impairing glycolysis. This hampers the ubiquitination and degradation of p35, favoring its cleavage to p25, which hyperactivates CDK5 and interferes with the GSK3β-induced degradation of β-catenin. CDK5 contributes to neuronal cell death while β-catenin enters the neuronal nucleus and re-activates the cell cycle machinery. Unable to successfully divide, the neuron instead enters a senescent-like state. These findings offer a direct connection between peripheral hyperinsulinemia, as found in prediabetes, age-related neurodegeneration and cognitive decline. The implications for neurodegenerative conditions such as Alzheimer’s disease are described.

In addition to providing well-characterized excitatory inputs, the entorhinal cortex also sends long-range inhibitory projections to the hippocampus. Basu et al. described this input in detail and characterized its role for learning and memory. Multimodal sensory stimuli activate long-range inhibitory input in vivo. This input enables precisely timed information transfer within the cortico-hippocampal circuit. In this way, long-range inhibitory projections play an important role in providing specificity of fear conditioning, and thus help prevent overgeneralization. Science , this issue p. 10.1126/science.aaa5694 Inhibitory inputs from the lateral entorhinal cortex help to make contextual memory associations specific. The cortico-hippocampal circuit is critical for storage of associational memories. Most studies have focused on the role in memory storage of the excitatory projections from entorhinal cortex to hippocampus. However, entorhinal cortex also sends inhibitory projections, whose role in memory storage and cortico-hippocampal activity remains largely unexplored. We found that these long-range inhibitory projections enhance the specificity of contextual and object memory encoding. At the circuit level, these γ-aminobutyric acid (GABA)–releasing projections target hippocampal inhibitory neurons and thus act as a disinhibitory gate that transiently promotes the excitation of hippocampal CA1 pyramidal neurons by suppressing feedforward inhibition. This enhances the ability of CA1 pyramidal neurons to fire synaptically evoked dendritic spikes and to generate a temporally precise form of heterosynaptic plasticity. Long-range inhibition from entorhinal cortex may thus increase the precision of hippocampal-based long-term memory associations by assessing the salience of mnemonic information to the immediate sensory input.

Here the author shows that an unstructured, sparsely connected network of model spiking neurons can display two different types of asynchronous activity: one in which an external input leads to a highly redundant response of different neurons that favors information transmission and another in which the firing rates of individual neurons fluctuate strongly in time and across neurons to provide a substrate for complex information processing. Asynchronous activity in balanced networks of excitatory and inhibitory neurons is believed to constitute the primary medium for the propagation and transformation of information in the neocortex. Here we show that an unstructured, sparsely connected network of model spiking neurons can display two fundamentally different types of asynchronous activity that imply vastly different computational properties. For weak synaptic couplings, the network at rest is in the well-studied asynchronous state, in which individual neurons fire irregularly at constant rates. In this state, an external input leads to a highly redundant response of different neurons that favors information transmission but hinders more complex computations. For strong couplings, we find that the network at rest displays rich internal dynamics, in which the firing rates of individual neurons fluctuate strongly in time and across neurons. In this regime, the internal dynamics interact with incoming stimuli to provide a substrate for complex information processing and learning.

Gamma oscillations (~30 to 100 Hz) provide a fundamental mechanism of information processing during sensory perception, motor behavior, and memory formation by coordination of neuronal activity in networks of the hippocampus and neocortex. We review the cellular mechanisms of gamma oscillations about the underlying neuroenergetics, i.e., high oxygen consumption rate and exquisite sensitivity to metabolic stress during hypoxia or poisoning of mitochondrial oxidative phosphorylation. Gamma oscillations emerge from the precise synaptic interactions of excitatory pyramidal cells and inhibitory GABAergic interneurons. In particular, specialized interneurons such as parvalbumin-positive basket cells generate action potentials at high frequency (‘fast-spiking’) and synchronize the activity of numerous pyramidal cells by rhythmic inhibition (‘clockwork’). As prerequisites, fast-spiking interneurons have unique electrophysiological properties and particularly high energy utilization, which is reflected in the ultrastructure by enrichment with mitochondria and cytochrome c oxidase, most likely needed for extensive membrane ion transport and γ-aminobutyric acid metabolism. This supports the hypothesis that highly energized fast-spiking interneurons are a central element for cortical information processing and may be critical for cognitive decline when energy supply becomes limited (‘interneuron energy hypothesis’). As a clinical perspective, we discuss the functional consequences of metabolic and oxidative stress in fast-spiking interneurons in aging, ischemia, Alzheimer's disease, and schizophrenia.

Evaluating odor blends in sensory processing is a crucial step for signal recognition and execution of behavioral decisions. Using behavioral assays and 2-photon imaging, we have characterized the neural and behavioral correlates of mixture perception in the olfactory system of Drosophila . Mixtures of odors with opposing valences elicit strong inhibition in certain attractant-responsive input channels. This inhibition correlates with reduced behavioral attraction. We demonstrate that defined subsets of GABAergic interneurons provide the neuronal substrate of this computation at pre- and postsynaptic loci via GABA B - and GABA A receptors, respectively. Intriguingly, manipulation of single input channels by silencing and optogenetic activation unveils a glomerulus-specific crosstalk between the attractant- and repellent-responsive circuits. This inhibitory interaction biases the behavioral output. Such a form of selective lateral inhibition represents a crucial neuronal mechanism in the processing of conflicting sensory information. Fruit flies need to appropriately respond to mixtures of attractive and repellent odors in their natural environment. Here, the authors propose that lateral inhibition between glomeruli activated by attractants or repulsive odors mediates the appropriate response.