Sound-driven synaptic inhibition in primary visual cortex

Multimodal objects and events activate many sensory cortical areas simultaneously. This is possibly reflected in reciprocal modulations of neuronal activity, even at the level of primary cortical areas. However, the synaptic character of these interareal interactions, and their impact on synaptic and behavioral sensory responses are unclear. Here, we found that activation of auditory cortex by a noise burst drove local GABAergic inhibition on supragranular pyramids of the mouse primary visual cortex, via cortico-cortical connections. This inhibition was generated by sound-driven excitation of a limited number of cells in infragranular visual cortical neurons. Consequently, visually driven synaptic and spike responses were reduced upon bimodal stimulation. Also, acoustic stimulation suppressed conditioned behavioral responses to a dim flash, an effect that was prevented by acute blockade of GABAergic transmission in visual cortex. Thus, auditory cortex activation by salient stimuli degrades potentially distracting sensory processing in visual cortex by recruiting local, translaminar, inhibitory circuits.     

Decline in the Recovery from Synaptic Depression in Heavier Aplysia Results from Decreased Serotonin-Induced Novel PKC Activation

The defensive withdrawal reflexes of Aplysia are important behaviors for protecting the animal from predation. Habituation and dishabituation allow for experience-dependent tuning of these reflexes and the mechanisms underlying these forms of behavioral plasticity involve changes in transmitter release from the sensory to motor neuron synapses through homosynaptic depression and the serotonin-mediated recovery from depression, respectively. Interestingly, dishabituation is reduced in older animals with no corresponding change in habituation. Here we show that the cultured sensory neurons of heavier animals (greater than 120g) that form synaptic connections with motor neurons have both reduced recovery from depression and reduced novel PKC Apl II activation with 5HT. The decrease in the recovery from depression correlated better with the size of the animal than the age of the animal. Much of this change in PKC activation and synaptic facilitation following depression can be rescued by direct activation of PKC Apl II with phorbol dibutyrate, suggesting a change in the signal transduction pathway upstream of PKC Apl II activation in the sensory neurons of larger animals.     

A "sample-and-hold" pulse-counting integrator as a mechanism for graded memory underlying sensorimotor adaptation

The mechanisms behind the induction of cellular correlates of memory by sensory input and their contribution to meaningful behavioral changes are largely unknown. We previously reported a graded memory in the form of sensorimotor adaptation in the electromotor output of electric fish. Here we show that the mechanism for this adaptation is a synaptically induced long-lasting shift in intrinsic neuronal excitability. This mechanism rapidly integrates hundreds of spikes in a second, or gradually integrates the same number of spikes delivered over tens of minutes. Thus, this mechanism appears immune to frequency-dependent fluctuations in input and operates as a simple pulse counter over a wide range of time scales, enabling it to transduce graded sensory information into a graded memory and a corresponding change in the behavioral output. This adaptation is based on an NMDA receptor-mediated change in intrinsic excitability of the postsynaptic neurons involving the Ca2+-dependent activation of TRP channels.     

A critical role of toll-like receptor 2 in nerve injury-induced spinal cord glial cell activation and pain hypersensitivity

The activation of spinal cord glial cells has been implicated in the development of neuropathic pain upon peripheral nerve injury. The molecular mechanisms underlying glial cell activation, however, have not been clearly elucidated. In this study, we found that damaged sensory neurons induce the expression of tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, and inducible nitric-oxide synthase genes in spinal cord glial cells, which is implicated in the development of neuropathic pain. Studies using primary glial cells isolated from toll-like receptor 2 knock-out mice indicate that damaged sensory neurons activate glial cells via toll-like receptor 2. In addition, behavioral studies using toll-like receptor 2 knock-out mice demonstrate that the expression of toll-like receptor 2 is required for the induction of mechanical allodynia and thermal hyperalgesia due to spinal nerve axotomy. The nerve injury-induced spinal cord microglia and astrocyte activation is reduced in the toll-like receptor 2 knock-out mice. Similarly, the nerve injury-induced pro-inflammatory gene expression in the spinal cord is also reduced in the toll-like receptor 2 knock-out mice. These data demonstrate that toll-like receptor 2 contributes to the nerve injury-induced spinal cord glial cell activation and subsequent pain hypersensitivity.     

Driving opposing behaviors with ensembles of piriform neurons

Anatomic and physiologic studies have suggested a model in which neurons of the piriform cortex receive convergent input from random collections of glomeruli. In this model, odor representations can only be afforded behavioral significance upon experience. We have devised an experimental strategy that permits us to ask whether the activation of an arbitrarily chosen subpopulation of neurons in piriform cortex can elicit different behavioral responses dependent upon learning. Activation of a small subpopulation of piriform neurons expressing channelrhodopsin at multiple loci in the piriform cortex, when paired with reward or shock, elicits either appetitive or aversive behavior. Moreover, we demonstrate that different subpopulations of piriform neurons expressing ChR2 can be discriminated and independently entrained to elicit distinct behaviors. These observations demonstrate that the piriform cortex is sufficient to elicit learned behavioral outputs in the absence of sensory input. These data imply that the piriform does not use spatial order to map odorant identity or behavioral output.     

Cortical network reorganization guided by sensory input features

 Sensory experience alters the functional organization of cortical networks. Previous studies using behavioral training motivated by aversive or rewarding stimuli have demonstrated that cortical plasticity is specific to salient inputs in the sensory environment. Sensory experience associated with electrical activation of the basal forebrain (BasF) generates similar input specific plasticity. By directly engaging plasticity mechanisms and avoiding extensive behavioral training, BasF stimulation makes it possible to efficiently explore how specific sensory features contribute to cortical plasticity. This review summarizes our observations that cortical networks employ a variety of strategies to improve the representation of the sensory environment. Different combinations of receptive-field, temporal, and spectrotemporal plasticity were generated in primary auditory cortex neurons depending on the pitch, modulation rate, and order of sounds paired with BasF stimulation. Simple tones led to map expansion, while modulated tones altered the maximum cortical following rate. Exposure to complex acoustic sequences led to the development of combination-sensitive responses. This remodeling of cortical response characteristics may reflect changes in intrinsic cellular mechanisms, synaptic efficacy, and local neuronal connectivity. The intricate relationship between the pattern of sensory activation and cortical plasticity suggests that network-level rules alter the functional organization of the cortex to generate the most behaviorally useful representation of the sensory environment. Received: 14 January 2002 / Accepted: 15 March 2002 Correspondence to: M.P. Kilgard (e-mail: kilgard@utdallas.edu, Tel.: +1-972-8832345, Fax: +1-972-8832491)     

Regulation of body size and behavioral state of C. elegans by sensory perception and the EGL-4 cGMP-dependent protein kinase

The growth and behavior of higher organisms depend on the accurate perception and integration of sensory stimuli by the nervous system. We show that defects in sensory perception in C. elegans result in abnormalities in the growth of the animal and in the expression of alternative behavioral states. Our analysis suggests that sensory neurons modulate neural or neuroendocrine functions, regulating both bodily growth and behavioral state. We identify genes likely to be required for these functions downstream of sensory inputs. Here, we characterize one of these genes as egl-4, which we show encodes a cGMP-dependent protein kinase. We demonstrate that this cGMP-dependent kinase functions in neurons of C. elegans to regulate multiple developmental and behavioral processes including the orchestrated growth of the animal and the expression of particular behavioral states.     

下丘脑-垂体-肾上腺皮质轴应激反应的中枢控制

应激反应是所有生物对紧张性事件的适应性反应,对生物的存活具有十分重要的意义。应激反应的主要特征是下丘脑－垂体－肾上腺皮质（ＨＰＡ）轴激活。ＨＰＨ轴激活的呆区控制十分复杂。海马参与整合感知的信息、解释环境信息的意义及定调行为反应和神经内分泌反应。杏仁核是应激性行为反应以及自主神经和神经内分泌反应的行旅地部位。下丘脑室６ 有直接激活ＨＰＡ轴的作用。负反馈机制、下丘脑局部回路和细胞因子也可能参与了调节Ｈ     

Behavioral functions of serotonin and octopamine: some paradoxes of comparative physiology

Evaluation of recent data on monoaminergic control of invertebrate behavior suggests that behavioral functions of serotonin in molluscs and octopamine in insects are remarkably similar. Specifically, in the respective taxa, these monoamines are responsible for activation of food searching and intense locomotion, increase in food consumption and general activity, enhancement of cardial and respiratory rhythms, facilitation of learning, sensitization of sensory circuits. At the same time, in insects, behavioral effects of serotonin are opposite to those of octopamine. It seems thus that two monoamines have exchanged their behavioral roles in the two major invertebrate taxa. Possible reasons of this paradoxical inversion touches inevitably upon basic questions of signal molecular evolution.     

Negative regulation and gain control of sensory neurons by the C. elegans calcineurin TAX-6

Animals sense and adapt to variable environments by regulating appropriate sensory signal transduction pathways. Here, we show that calcineurin plays a key role in regulating the gain of sensory neuron responsiveness across multiple modalities. C. elegans animals bearing a loss-of-function mutation in TAX-6, a calcineurin A subunit, exhibit pleiotropic abnormalities, including many aberrant sensory behaviors. The tax-6 mutant defect in thermosensation is consistent with hyperactivation of the AFD thermosensory neurons. Conversely, constitutive activation of TAX-6 causes a behavioral phenotype consistent with inactivation of AFD neurons. In olfactory neurons, the impaired olfactory response of tax-6 mutants to an AWC-sensed odorant is caused by hyperadaptation, which is suppressible by a mutation causing defective olfactory adaptation. Taken together, our results suggest that stimulus-evoked calcium entry activates calcineurin, which in turn negatively regulates multiple aspects of sensory signaling.     

Attentional enhancement via selection and pooling of early sensory responses in human visual cortex

The computational processes by which attention improves behavioral performance were characterized by measuring visual cortical activity with functional magnetic resonance imaging as humans performed a contrast-discrimination task with focal and distributed attention. Focal attention yielded robust improvements in behavioral performance accompanied by increases in cortical responses. Quantitative analysis revealed that if performance were limited only by the sensitivity of the measured sensory signals, the improvements in behavioral performance would have corresponded to an unrealistically large reduction in response variability. Instead, behavioral performance was well characterized by a pooling and selection process for which the largest sensory responses, those most strongly modulated by attention, dominated the perceptual decision. This characterization predicts that high-contrast distracters that evoke large responses should negatively impact behavioral performance. We tested and confirmed this prediction. We conclude that attention enhanced behavioral performance predominantly by enabling efficient selection of the behaviorally relevant sensory signals.     

Extrinsic embryonic sensory stimulation alters multimodal behavior and cellular activation

Embryonic vision is generated and maintained by spontaneous neuronal activation patterns, yet extrinsic stimulation also sculpts sensory development. Because the sensory and motor systems are interconnected in embryogenesis, how extrinsic sensory activation guides multimodal differentiation is an important topic. Further, it is unknown whether extrinsic stimulation experienced near sensory sensitivity onset contributes to persistent brain changes, ultimately affecting postnatal behavior. To determine the effects of extrinsic stimulation on multimodal development, we delivered auditory stimulation to bobwhite quail groups during early, middle, or late embryogenesis, and then tested postnatal behavioral responsiveness to auditory or visual cues. Auditory preference tendencies were more consistently toward the conspecific stimulus for animals stimulated during late embryogenesis. Groups stimulated during middle or late embryogenesis showed altered postnatal species-typical visual responsiveness, demonstrating a persistent multimodal effect. We also examined whether auditory-related brain regions are receptive to extrinsic input during middle embryogenesis by measuring postnatal cellular activation. Stimulated birds showed a greater number of ZENK-immunopositive cells per unit volume of brain tissue in deep optic tectum, a midbrain region strongly implicated in multimodal function. We observed similar results in the medial and caudomedial nidopallia in the telencephalon. There were no ZENK differences between groups in inferior colliculus or in caudolateral nidopallium, avian analog to prefrontal cortex. To our knowledge, these are the first results linking extrinsic stimulation delivered so early in embryogenesis to changes in postnatal multimodal behavior and cellular activation. The potential role of competitive interactions between the sensory and motor systems is discussed.     

TRPV1 and TRPA1 Mediate Peripheral Nitric Oxide-Induced Nociception in Mice

Nitric oxide (NO) can induce acute pain in humans and plays an important role in pain sensitization caused by inflammation and injury in animal models. There is evidence that NO acts both in the central nervous system via a cyclic GMP pathway and in the periphery on sensory neurons through unknown mechanisms. It has recently been suggested that TRPV1 and TRPA1, two polymodal ion channels that sense noxious stimuli impinging on peripheral nociceptors, are activated by NO in heterologous systems. Here, we investigate the relevance of this activation. We demonstrate that NO donors directly activate TRPV1 and TRPA1 in isolated inside-out patch recordings. Cultured primary sensory neurons display both TRPV1- and TRPA1-dependent responses to NO donors. BH4, an essential co-factor for NO production, causes activation of a subset of DRG neurons as assayed by calcium imaging, and this activation is at least partly dependent on nitric oxide synthase activity. We show that BH4-induced calcium influx is ablated in DRG neurons from TRPA1/TRPV1 double knockout mice, suggesting that production of endogenous levels of NO can activate these ion channels. In behavioral assays, peripheral NO-induced nociception is compromised when TRPV1 and TRPA1 are both ablated. These results provide genetic evidence that the peripheral nociceptive action of NO is mediated by both TRPV1 and TRPA1.     

Secretin Activates Visceral Brain Regions in the Rat Including Areas Abnormal in Autism

1. The aim of this study was to determine whether central networks are involved in the presumptive behavioral and autonomic regulatory actions of secretin, a gut hormone that has been reported to have ameliorative effects in autistic children.2. Central neural responses monitored by regional c-fos gene expression were examined in response to intracerebroventricular secretin injection in awake, freely-moving Sprague-Dawley rats. Tissue sections were incubated in an antibody to the c-fosgene product, Fos, and processed immunohistochemically.3. Qualitative differences in Fos immunoreactivity in stress adaptation and visceral representation areas of the brain were observed between secretin- and vehicle-infused age-matched pairs (n = 4 pairs). Secretin-activated regions include the area postrema, dorsal motor nucleus, medial region of the nucleus of the solitary tract and its relay station in the lateral tegmentum, locus ceruleus, ventral periaqueductal gray, periventricular thalamic nucleus, paraventricular hypothalamus magnocellularis, medial and central amygdala, lateral septal complex as well as ependymal and subependymal nuclei lining the third ventricle. Specific areas of the cerebral cortex were heavily labeled in secretin-treated rats, as compared to controls: the medial bank of the anterior prefrontal cortex, orbitofrontal cortex, the piriform cortex, and the anterior olfactory nucleus. Secretin attenuated Fos immunoreactivity in the dorsal periaqueductal gray, intralaminar thalamus, medial parvicellular compartment of the hypothalamus, supraoptic nucleus of the hypothalamus, lateral amygdala, motor cortex, and the somatosensory and association areas of the parietal cortex.4. Secretin alters the activity of structures involved in behavioral conditioning of stress adaptation and visceral reflex reactions. This study predicts a possible cellular mechanism, activation of third ventricular ependymal and subependymal cells, as well as central regulatory actions of secretin. The physiological effects of secretin on behavioral, endocrine, autonomic and sensory neuronal activation patterns, together, contribute to central c-fos activation. Secretin alters the activity of structures involved in behavioral conditioning of stress adaptation and visceral reflex reactions. This study predicts a possible cellular mechanism, activation of third ventricular ependymal and subependymal cells, and central regulatory actions of secretin. The physiological effects of secretin on behavioral, endocrine, autonomic and sensory neuronal activation patterns, together, contribute to central c-fos activation. These findings mandate further investigation of secretin as a brain/gut stress regulatory hormone.     

Decision, sensation, and habituation: a multi-layer dynamic field model for Inhibition of Return

Inhibition of Return (IOR) is one of the most consistent and widely studied effects in experimental psychology. The effect refers to a delayed response to visual stimuli in a cued location after initial priming at that location. This article presents a dynamic field model for IOR. The model describes the evolution of three coupled activation fields. The decision field, inspired by the intermediate layer of the superior colliculus, receives endogenous input and input from a sensory field. The sensory field, inspired by earlier sensory processing, receives exogenous input. Habituation of the sensory field is implemented by a reciprocal coupling with a third field, the habituation field. The model generates IOR because, due to the habituation of the sensory field, the decision field receives a reduced target-induced input in cue-target-compatible situations. The model is consistent with single-unit recordings of neurons of monkeys that perform IOR tasks. Such recordings have revealed that IOR phenomena parallel the activity of neurons in the intermediate layer of the superior colliculus and that neurons in this layer receive reduced input in cue-target-compatible situations. The model is also consistent with behavioral data concerning temporal expectancy effects. In a discussion, the multi-layer dynamic field account of IOR is used to illustrate the broader view that behavior consists of a tuning of the organism to the environment that continuously and concurrently takes place at different spatiotemporal scales.     

Activation of Mu Opioid Receptors Sensitizes Transient Receptor Potential Vanilloid Type 1 (TRPV1) via β-Arrestin-2-Mediated Cross-Talk

The transient receptor potential family V1 channel (TRPV1) is activated by multiple stimuli, including capsaicin, acid, endovanilloids, and heat (>42C). Post-translational modifications to TRPV1 result in dynamic changes to the sensitivity of receptor activation. We have previously demonstrated that β-arrestin2 actively participates in a scaffolding mechanism to inhibit TRPV1 phosphorylation, thereby reducing TRPV1 sensitivity. In this study, we evaluated the effect of β-arrestin2 sequestration by G-protein coupled receptors (GPCRs) on thermal and chemical activation of TRPV1. Here we report that activation of mu opioid receptor by either morphine or DAMGO results in β-arrestin2 recruitment to mu opioid receptor in sensory neurons, while activation by herkinorin does not. Furthermore, treatment of sensory neurons with morphine or DAMGO stimulates β-arrestin2 dissociation from TRPV1 and increased sensitivity of the receptor. Conversely, herkinorin treatment has no effect on TRPV1 sensitivity. Additional behavioral studies indicate that GPCR-driven β-arrestin2 sequestration plays an important peripheral role in the development of thermal sensitivity. Taken together, the reported data identify a novel cross-talk mechanism between GPCRs and TRPV1 that may contribute to multiple clinical conditions.     

Local and global methods of assessing thermal nociception in Drosophila larvae

In this article, we demonstrate assays to study thermal nociception in Drosophila larvae. One assay involves spatially-restricted (local) stimulation of thermal nociceptors while the second involves a wholesale (global) activation of most or all such neurons. Together, these techniques allow visualization and quantification of the behavioral functions of Drosophila nociceptive sensory neurons. The Drosophila larva is an established model system to study thermal nociception, a sensory response to potentially harmful temperatures that is evolutionarily conserved across species. The advantages of Drosophila for such studies are the relative simplicity of its nervous system and the sophistication of the genetic techniques that can be used to dissect the molecular basis of the underlying biology In Drosophila, as in all metazoans, the response to noxious thermal stimuli generally involves a "nocifensive" aversive withdrawal to the presented stimulus. Such stimuli are detected through free nerve endings or nociceptors and the amplitude of the organismal response depends on the number of nociceptors receiving the noxious stimulus. In Drosophila, it is the class IV dendritic arborization sensory neurons that detect noxious thermal and mechanical stimuli in addition to their recently discovered role as photoreceptors. These neurons, which have been very well studied at the developmental level, arborize over the barrier epidermal sheet and make contacts with nearly all epidermal cells. The single axon of each class IV neuron projects into the ventral nerve cord of the central nervous system where they may connect to second-order neurons that project to the brain. Under baseline conditions, nociceptive sensory neurons will not fire until a relatively high threshold is reached. The assays described here allow the investigator to quantify baseline behavioral responses or, presumably, the sensitization that ensues following tissue damage. Each assay provokes distinct but related locomotory behavioral responses to noxious thermal stimuli and permits the researcher to visualize and quantify various aspects of thermal nociception in Drosophila larvae. The assays can be applied to larvae of desired genotypes or to larvae raised under different environmental conditions that might impact nociception. Since thermal nociception is conserved across species, the findings gleaned from genetic dissection in Drosophila will likely inform our understanding of thermal nociception in other species, including vertebrates.     

Reshaping sensory representations by task-specific brain states: Toward cortical circuit mechanisms

Perception is internally constructed by integrating brain states with external sensory inputs, a process depending on the topdown modulation of sensory representations. A wealth of earlier studies described task-dependent modulations of sensory cortex corroborating perceptual and behavioral phenomena. But only with recent technological advancements, the underlying circuit-level mechanisms began to be unveiled. We review recent progress along this line of research. It begins to be appreciated that topdown signals can encode various types of task-related information, ranging from task engagement, and category knowledge to decision execution; these signals are transferred via feedback pathways originating from distinct association cortices and interact with sensory cortical circuits. These plausible mechanisms support a broad range of computations from predictive coding to inference making, ultimately form dynamic percepts and endow behavioral flexibility.     

Behavioral and neuroplastic changes in the blind: evidence for functionally relevant cross-modal interactions.

The study of blind individuals provides insight into the brain re-organization and behavioral compensations that occur following sensory deprivation. While behavioral studies have yielded conflicting results in terms of performance levels within the remaining senses, deafferentation of visual cortical areas through peripheral blindness results in clear neuroplastic changes. Most striking is the activation of occipital cortex in response to auditory and tactile stimulation. Indeed, parts of the "unimodal" visual cortex are recruited by other sensory modalities to process sensory information in a functionally relevant manner. In addition, a larger area of the sensorimotor cortex is devoted to the representation of the reading finger in blind Braille readers. The "visual" function of the deafferented occipital cortex is also altered, where transcranial magnetic stimulation-induced phosphenes can be elicited in only 20% of blind subjects. The neural mechanisms underlying these changes remain elusive but recent data showing rapid cross-modal plasticity in blindfolded, sighted subjects argue against the establishment of new connections to explain cross-modal interactions in the blind. Rather, latent pathways that participate in multisensory percepts in sighted subjects might be unmasked and may be potentiated in the event of complete loss of visual input. These issues have important implications for the development of visual prosthesis aimed at restoring some degree of vision in the blind.     

An "enactive" approach to integrative and comparative biology: thoughts on the table

We discuss the concept of Enaction as originally proposed by Varela. We attempt to exemplify through two specific topics, sensory ecology and behavior, as well as physiological and behavioral ecology, on which the enactive approach is based. We argue that sensory physiology allows us to explore the biological and cognitive meaning of animal 'private' sensory channels, beyond the scope of our own sensory capacity. Furthermore, after analyzing the interplay between factors that may impose limits upon an animal's use of time and energy, we call for a program of research in integrative and comparative biology that simultaneously considers evolutionary ecology (including physiological and behavioral ecology) and neurobiology (including cognitive mechanisms as well structural design). We believe that this approach represents a shift in scientific attitude among biologists concerning the place of biological and ecological topics in studies of integrative and comparative biology and biological diversity and vice versa.