Arousal responses linked to locus coeruleus noradrenergic (LC-NA) activity affect cognition. However, the mechanisms that control modes of LC-NA activity remain unknown. Here, we reveal a local ...population of GABAergic neurons (LC-GABA) capable of modulating LC-NA activity and arousal. Retrograde tracing shows that inputs to LC-GABA and LC-NA neurons arise from similar regions, though a few regions provide differential inputs to one subtype over the other. Recordings in the locus coeruleus demonstrate two modes of LC-GABA responses whereby spiking is either correlated or broadly anticorrelated with LC-NA responses, reflecting anatomically similar and functionally coincident inputs, or differential and non-coincident inputs, to LC-NA and LC-GABA neurons. Coincident inputs control the gain of LC-NA-mediated arousal responses, whereas non-coincident inputs, such as from the prefrontal cortex to the locus coeruleus, alter global arousal levels. These findings demonstrate distinct modes by which an inhibitory locus coeruleus circuit regulates arousal in the brain.
GABAergic inhibition shapes the connectivity, activity and plasticity of the brain. A series of exciting new discoveries provides compelling evidence that disruptions in a number of key facets of ...GABAergic inhibition have critical roles in the aetiology of neurodevelopmental disorders (NDDs). These facets include the generation, migration and survival of GABAergic neurons, the formation of GABAergic synapses and circuit connectivity, and the dynamic regulation of the efficacy of GABAergic signalling through neuronal chloride transporters. In this Review, we discuss recent work that elucidates the functions and dysfunctions of GABAergic signalling in health and disease, that uncovers the contribution of GABAergic neural circuit dysfunction to NDD aetiology and that leverages such mechanistic insights to advance precision medicine for the treatment of NDDs.
Research in the genetics of neurodevelopmental disorders such as autism suggests that several hundred genes are likely risk factors for these disorders. This heterogeneity presents a challenge and an ...opportunity at the same time. Although the exact identity of many of the genes remains to be discovered, genes identified to date encode proteins that play roles in certain conserved pathways: protein synthesis, transcriptional and epigenetic regulation, and synaptic signaling. The next generation of research in neurodevelopmental disorders must address the neural circuitry underlying the behavioral symptoms and comorbidities, the cell types playing critical roles in these circuits, and common intercellular signaling pathways that link diverse genes. Results from clinical trials have been mixed so far. Only when we can leverage the heterogeneity of neurodevelopmental disorders into precision medicine will the mechanism-based therapeutics for these disorders start to unlock success.
Two-photon microscopy is used to image neuronal activity, but has severe limitations for studying deeper cortical layers. Here, we developed a custom three-photon microscope optimized to image a ...vertical column of the cerebral cortex > 1 mm in depth in awake mice with low (<20 mW) average laser power. Our measurements of physiological responses and tissue-damage thresholds define pulse parameters and safety limits for damage-free three-photon imaging. We image functional visual responses of neurons expressing GCaMP6s across all layers of the primary visual cortex (V1) and in the subplate. These recordings reveal diverse visual selectivity in deep layers: layer 5 neurons are more broadly tuned to visual stimuli, whereas mean orientation selectivity of layer 6 neurons is slightly sharper, compared to neurons in other layers. Subplate neurons, located in the white matter below cortical layer 6 and characterized here for the first time, show low visual responsivity and broad orientation selectivity.
Cholinergic modulation of cortex powerfully influences information processing and brain states, causing robust desynchronization of local field potentials and strong decorrelation of responses ...between neurons. We found that intracortical cholinergic inputs to mouse visual cortex specifically and differentially drive a defined cortical microcircuit: they facilitate somatostatin-expressing (SOM) inhibitory neurons that in turn inhibit parvalbumin-expressing inhibitory neurons and pyramidal neurons. Selective optogenetic inhibition of SOM responses blocked desynchronization and decorrelation, demonstrating that direct cholinergic activation of SOM neurons is necessary for this phenomenon. Optogenetic inhibition of vasoactive intestinal peptide-expressing neurons did not block desynchronization, despite these neurons being activated at high levels of cholinergic drive. Direct optogenetic SOM activation, independent of cholinergic modulation, was sufficient to induce desynchronization. Together, these findings demonstrate a mechanistic basis for temporal structure in cortical populations and the crucial role of neuromodulatory drive in specific inhibitory-excitatory circuits in actively shaping the dynamics of neuronal activity.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Mapping specific sensory features to future motor actions is a crucial capability of mammalian nervous systems. We investigated the role of visual (V1), posterior parietal (PPC), and frontal motor ...(fMC) cortices for sensorimotor mapping in mice during performance of a memory-guided visual discrimination task. Large-scale calcium imaging revealed that V1, PPC, and fMC neurons exhibited heterogeneous responses spanning all task epochs (stimulus, delay, response). Population analyses demonstrated unique encoding of stimulus identity and behavioral choice information across regions, with V1 encoding stimulus, fMC encoding choice even early in the trial, and PPC multiplexing the two variables. Optogenetic inhibition during behavior revealed that all regions were necessary during the stimulus epoch, but only fMC was required during the delay and response epochs. Stimulus identity can thus be rapidly transformed into behavioral choice, requiring V1, PPC, and fMC during the transformation period, but only fMC for maintaining the choice in memory prior to execution.
Plasticity of cortical responses in vivo involves activity-dependent changes at synapses, but the manner in which different forms of synaptic plasticity act together to create functional changes in ...neurons remains unknown. We found that spike timing-induced receptive field plasticity of visual cortex neurons in mice is anchored by increases in the synaptic strength of identified spines. This is accompanied by a decrease in the strength of adjacent spines on a slower time scale. The locally coordinated potentiation and depression of spines involves prominent AMPA receptor redistribution via targeted expression of the immediate early gene product Arc. Hebbian strengthening of activated synapses and heterosynaptic weakening of adjacent synapses thus cooperatively orchestrate cell-wide plasticity of functional neuronal responses.
Synapses store information by long-lasting modifications of their structure and molecular composition, but the precise chronology of these changes has not been studied at single-synapse resolution in ...real time. Here we describe the spatiotemporal reorganization of postsynaptic substructures during long-term potentiation (LTP) at individual dendritic spines. Proteins translocated to the spine in four distinct patterns through three sequential phases. In the initial phase, the actin cytoskeleton was rapidly remodeled while active cofilin was massively transported to the spine. In the stabilization phase, cofilin formed a stable complex with F-actin, was persistently retained at the spine, and consolidated spine expansion. In contrast, the postsynaptic density (PSD) was independently remodeled, as PSD scaffolding proteins did not change their amount and localization until a late protein synthesis-dependent third phase. Our findings show how and when spine substructures are remodeled during LTP and explain why synaptic plasticity rules change over time.
•Postsynaptic proteins are reorganized during LTP in three sequential phases•Cofilin is rapidly, persistently enriched in the spine via a stable F-actin complex•Cofilin signaling pathway is necessary for the maintenance of spine expansion•Delayed PSD growth is spine expansion independent but protein synthesis dependent
Bosch et al. describe the spatiotemporal reorganization of postsynaptic substructures during potentiation at single dendritic spines. They uncover the late-phase growth of the postsynaptic density and the unique dynamics of cofilin, which play a critical role in consolidating spine growth.
Probing gene function in the mammalian brain can be greatly assisted with methods to manipulate the genome of neurons in vivo. The clustered, regularly interspaced, short palindromic repeats ...(CRISPR)-associated endonuclease (Cas)9 from Streptococcus pyogenes (SpCas9) can be used to edit single or multiple genes in replicating eukaryotic cells, resulting in frame-shifting insertion/deletion (indel) mutations and subsequent protein depletion. Here, we delivered SpCas9 and guide RNAs using adeno-associated viral (AAV) vectors to target single (Mecp2) as well as multiple genes (Dnmt1, Dnmt3a and Dnmt3b) in the adult mouse brain in vivo. We characterized the effects of genome modifications in postmitotic neurons using biochemical, genetic, electrophysiological and behavioral readouts. Our results demonstrate that AAV-mediated SpCas9 genome editing can enable reverse genetic studies of gene function in the brain.
Astrocytes, the most abundant glial cell in the brain, play critical roles in metabolic and homeostatic functions of the Nervous System; however, their participation in coding information and ...cognitive processes has been largely ignored. The strategic position of astrocyte processes facing synapses and the astrocyte ability to uptake neurotransmitters and release neuroactive substances, so-called "gliotransmitters", provide the scenario for prolific neuron-astrocyte signaling. From studies at single-cell level to animal behavior, recent advances in technology and genetics have revealed the impact of astrocyte activity in brain function from cellular and synaptic physiology, neuronal circuits to behavior. The present review critically discusses the consequences of astrocyte signaling on synapses and networks, as well as its impact on neuronal information processing, showing that some crucial brain functions arise from the coordinated activity of neuron-glia networks.
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