The gastrointestinal tract is the only internal organ to have evolved with its own independent nervous system, known as the enteric nervous system (ENS). This Review provides an update on advances ...that have been made in our understanding of how neurons within the ENS coordinate sensory and motor functions. Understanding this function is critical for determining how deficits in neurogenic motor patterns arise. Knowledge of how distension or chemical stimulation of the bowel evokes sensory responses in the ENS and central nervous system have progressed, including critical elements that underlie the mechanotransduction of distension-evoked colonic peristalsis. Contrary to original thought, evidence suggests that mucosal serotonin is not required for peristalsis or colonic migrating motor complexes, although it can modulate their characteristics. Chemosensory stimuli applied to the lumen can release substances from enteroendocrine cells, which could subsequently modulate ENS activity. Advances have been made in optogenetic technologies, such that specific neurochemical classes of enteric neurons can be stimulated. A major focus of this Review will be the latest advances in our understanding of how intrinsic sensory neurons in the ENS detect and respond to sensory stimuli and how these mechanisms differ from extrinsic sensory nerve endings in the gut that underlie the gut-brain axis.
We examined whether consciously undetected fear signals engage a collateral brainstem pathway to the amygdala and prefrontal cortex in the intact human brain, using functional neuroimaging. ...‘Blindsight’ lesion patients can respond to visual fear signals independently from conscious experience, suggesting that these signals reach the amygdala via a direct pathway that bypasses the primary visual cortex. Electrophysiological evidence points to concomitant involvement of prefrontal regions in automatic orienting to subliminal signals of fear, which may reflect innervation arising from brainstem arousal systems. To approximate blindsight in 22 healthy subjects, facial signals of fear were presented briefly (16.7 ms) and masked such that conscious detection was prevented. Results revealed that subliminal fear signals elicited activity in the brainstem region encompassing the superior colliculus and locus coeruleus, pulvinar and amygdala, and in fronto-temporal regions associated with orienting. These findings suggest that crude sensory input from the superior colliculo-pulvinar visual pathway to the amygdala may allow for sufficient appraisal of fear signals to innervate the locus coeruleus. The engagement of the locus coeruleus could explain the observation of diffuse fronto-temporal cortical activity, given its role in evoking collateral ascending noradrenergic efferents to the subcortical amygdala and prefrontal cortex. This network may represent an evolutionary adaptive neural ‘alarm’ system for rapid alerting to sources of threat, without the need for conscious appraisal.
Salient cues can prompt the rapid interruption of planned actions. It has been proposed that fast, reactive behavioral inhibition involves specific basal ganglia pathways, and we tested this by ...comparing activity in multiple rat basal ganglia structures during performance of a stop-signal task. Subthalamic nucleus (STN) neurons exhibited low-latency responses to 'Stop' cues, irrespective of whether actions were canceled or not. By contrast, neurons downstream in the substantia nigra pars reticulata (SNr) only responded to Stop cues in trials with successful cancellation. Recordings and simulations together indicate that this sensorimotor gating arises from the relative timing of two distinct inputs to neurons in the SNr dorsolateral 'core' subregion: cue-related excitation from STN and movement-related inhibition from striatum. Our results support race models of action cancellation, with stopping requiring Stop-cue information to be transmitted from STN to SNr before increased striatal input creates a point of no return.
Abstract Estrogens have direct effects on the brain areas controlling cognition. One of the most studied of these regions is the dorsal hippocampal formation, which governs the formation of spatial ...and episodic memories. In laboratory animals, most investigators report that estrogen enhances synaptic plasticity and improves performance on hippocampal-dependent cognitive behaviors. This review summarizes work conducted in our laboratory and others toward identifying estrogen’s actions in the hippocampal formation, and the mechanisms for these actions. Physiologic and pharmacologic estrogen affects cognitive behavior in mammals, which may be applicable to human health and disease. The effects of estrogen in the hippocampal formation that lead to modulation of hippocampal function include effects on cell morphology, synapse formation, signaling, and excitability that have been studied in laboratory mice, rats, and primates. Finally, estrogen may signal through both nuclear and extranuclear hippocampal estrogen receptors to achieve its downstream effects.
The mitosis-to-interphase transition involves dramatic cellular reorganization from a state that supports chromosome segregation to a state that complies with all functions of an interphase cell. ...This process, termed mitotic exit, depends on the removal of mitotic phosphorylations from a broad range of substrates. Mitotic exit regulation involves inactivation of mitotic kinases and activation of counteracting protein phosphatases. The key mitotic exit phosphatase in budding yeast, Cdc14, is now well understood. By contrast, in animal cells, it is now emerging that mitotic exit relies on distinct regulatory networks, including the protein phosphatases PP1 and PP2A.
How learning enhances neural representations for behaviorally relevant stimuli via activity changes of cortical cell types remains unclear. We simultaneously imaged responses of pyramidal cells (PYR) ...along with parvalbumin (PV), somatostatin (SOM), and vasoactive intestinal peptide (VIP) inhibitory interneurons in primary visual cortex while mice learned to discriminate visual patterns. Learning increased selectivity for task-relevant stimuli of PYR, PV and SOM subsets but not VIP cells. Strikingly, PV neurons became as selective as PYR cells, and their functional interactions reorganized, leading to the emergence of stimulus-selective PYR-PV ensembles. Conversely, SOM activity became strongly decorrelated from the network, and PYR-SOM coupling before learning predicted selectivity increases in individual PYR cells. Thus, learning differentially shapes the activity and interactions of multiple cell classes: while SOM inhibition may gate selectivity changes, PV interneurons become recruited into stimulus-specific ensembles and provide more selective inhibition as the network becomes better at discriminating behaviorally relevant stimuli.
The general view on the functional role of the monkey inferior parietal lobule (IPL) convexity mainly derives from studies carried out more than two decades ago and does not account for the ...functional complexity suggested by more recent neuroanatomical findings. We investigated this issue by recording multi‐ and single units in the IPL convexity of two monkeys and characterizing their somatosensory, visual and motor responses, using a naturalistic (ethologically relevant) approach. These properties were then matched with IPL cytoarchitectonic parcellation. A further aim of this study was to describe the general properties and the localization of IPL mirror neurons, until now not investigated in detail. Results showed that each studied cytoarchitectonic subdivision of the IPL (PF, PFG, PG) is characterized by specific sensory and motor properties. A key feature of the recorded motor neurons is that of coding goal‐directed motor acts. Motor responses are somatotopically organized in a rostro‐caudal fashion, with mouth, hand and arm represented in PF, PFG and PG, respectively, with a certain degree of overlap between adjacent representations. In each subdivision the motor activity is associated with specific somatosensory and visual responses, suggesting that each area organizes motor acts in different space sectors. Mirror neurons have been found mainly in area PFG and their general features appear to be very similar to those of ventral premotor mirror neurons. The present data suggest that the IPL plays an important role in both action organization and action understanding and should be considered part of the motor system.
The attenuation of ancestral pro-regenerative pathways may explain why humans do not efficiently regenerate damaged organs. Vertebrate lineages that exhibit robust regeneration, including the teleost ...zebrafish, provide insights into the maintenance of adult regenerative capacity. Using established models of spinal cord, heart, and retina regeneration, we discovered that zebrafish Treg-like (zTreg) cells rapidly homed to damaged organs. Conditional ablation of zTreg cells blocked organ regeneration by impairing precursor cell proliferation. In addition to modulating inflammation, infiltrating zTreg cells stimulated regeneration through interleukin-10-independent secretion of organ-specific regenerative factors (Ntf3: spinal cord; Nrg1: heart; Igf1: retina). Recombinant regeneration factors rescued the regeneration defects associated with zTreg cell depletion, whereas Foxp3a-deficient zTreg cells infiltrated damaged organs but failed to express regenerative factors. Our data delineate organ-specific roles for Treg cells in maintaining pro-regenerative capacity that could potentially be harnessed for diverse regenerative therapies.
•Treg cells are required for spinal cord, heart, and retina regeneration in zebrafish•Treg cells promote regeneration by producing tissue-specific growth factors•Pro-regenerative Treg cell activity is distinct from immunosuppressive functions•Zebrafish Foxp3a is essential for the production of tissue-specific growth factors
Hui et al. show that zebrafish regulatory T (zTreg) cells infiltrate damaged spinal cords, hearts, and retinas and are essential for robust regeneration. Infiltrating zTreg cells produce tissue-specific pro-regenerative factors that stimulate tissue-resident precursor cell proliferation, revealing new cellular targets for increasing regenerative capacity in poorly regenerating species.
Astrocytes may function as mediators of the impact of noradrenaline on neuronal function. Activation of glial α1-adrenergic receptors triggers rapid astrocytic Ca
elevation and facilitates synaptic ...plasticity, while activation of β-adrenergic receptors elevates cAMP levels and modulates memory consolidation. However, the dynamics of these processes in behaving mice remain unexplored, as do the interactions between the distinct second messenger pathways. Here we simultaneously monitored astrocytic Ca
and cAMP and demonstrate that astrocytic second messengers are regulated in a temporally distinct manner. In behaving mice, we found that while an abrupt facial air puff triggered transient increases in noradrenaline release and large cytosolic astrocytic Ca
elevations, cAMP changes were not detectable. By contrast, repeated aversive stimuli that lead to prolonged periods of vigilance were accompanied by robust noradrenergic axonal activity and gradual sustained cAMP increases. Our findings suggest distinct astrocytic signaling pathways can integrate noradrenergic activity during vigilance states to mediate distinct functions supporting memory.
Consensus across hundreds of published studies indicates that the same cortical regions are involved in many forms of cognitive control. Using functional magnetic resonance imaging (fMRI), we found ...that these coactive regions form a functionally connected cognitive control network (CCN). Network status was identified by convergent methods, including: high inter-regional correlations during rest and task performance, consistently higher correlations within the CCN than the rest of cortex, co-activation in a visual search task, and mutual sensitivity to decision difficulty. Regions within the CCN include anterior cingulate cortex/pre-supplementary motor area (ACC/pSMA), dorsolateral prefrontal cortex (DLPFC), inferior frontal junction (IFJ), anterior insular cortex (AIC), dorsal pre-motor cortex (dPMC), and posterior parietal cortex (PPC). We used a novel visual line search task which included periods when the probe stimuli were occluded but subjects had to maintain and update working memory in preparation for the sudden appearance of a probe stimulus. The six CCN regions operated as a tightly coupled network during the ‘non-occluded’ portions of this task, with all regions responding to probe events. In contrast, the network was differentiated during occluded search. DLPFC, not ACC/pSMA, was involved in target memory maintenance when probes were absent, while both regions became active in preparation for difficult probes at the end of each occluded period. This approach illustrates one way in which a neuronal network can be identified, its high functional connectivity established, and its components dissociated in order to better understand the interactive and specialized internal mechanisms of that network.
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