Gain control by layer six in cortical circuits of vision

After entering the cerebral cortex, sensory information spreads through six different horizontal neuronal layers that are interconnected by vertical axonal projections. It is believed that through these projections layers can influence each other's response to sensory stimuli, but the specific role that each layer has in cortical processing is still poorly understood. Here we show that layer six in the primary visual cortex of the mouse has a crucial role in controlling the gain of visually evoked activity in neurons of the upper layers without changing their tuning to orientation. This gain modulation results from the coordinated action of layer six intracortical projections to superficial layers and deep projections to the thalamus, with a substantial role of the intracortical circuit. This study establishes layer six as a major mediator of cortical gain modulation and suggests that it could be a node through which convergent inputs from several brain areas can regulate the earliest steps of cortical visual processing.     

Analgesia and hyperalgesia from GABA-mediated modulation of the cerebral cortex

It is known that pain perception can be altered by mood, attention and cognition, or by direct stimulation of the cerebral cortex, but we know little of the neural mechanisms underlying the cortical modulation of pain. One of the few cortical areas consistently activated by painful stimuli is the rostral agranular insular cortex (RAIC) where, as in other parts of the cortex, the neurotransmitter gamma-aminobutyric acid (GABA) robustly inhibits neuronal activity. Here we show that changes in GABA neurotransmission in the RAIC can raise or lower the pain threshold--producing analgesia or hyperalgesia, respectively--in freely moving rats. Locally increasing GABA, by using an enzyme inhibitor or gene transfer mediated by a viral vector, produces lasting analgesia by enhancing the descending inhibition of spinal nociceptive neurons. Selectively activating GABA(B)-receptor-bearing RAIC neurons produces hyperalgesia through projections to the amygdala, an area involved in pain and fear. Whereas most studies focus on the role of the cerebral cortex as the end point of nociceptive processing, we suggest that cerebral cortex activity can change the set-point of pain threshold in a top-down manner.     

Turning on and off recurrent balanced cortical activity

The vast majority of synaptic connections onto neurons in the cerebral cortex arise from other cortical neurons, both excitatory and inhibitory, forming local and distant 'recurrent' networks. Although this is a basic theme of cortical organization, its study has been limited largely to theoretical investigations, which predict that local recurrent networks show a proportionality or balance between recurrent excitation and inhibition, allowing the generation of stable periods of activity. This recurrent activity might underlie such diverse operations as short-term memory, the modulation of neuronal excitability with attention, and the generation of spontaneous activity during sleep. Here we show that local cortical circuits do indeed operate through a proportional balance of excitation and inhibition generated through local recurrent connections, and that the operation of such circuits can generate self-sustaining activity that can be turned on and off by synaptic inputs. These results confirm the long-hypothesized role of recurrent activity as a basic operation of the cerebral cortex.     

Rapid developmental switch in the mechanisms driving early cortical columnar networks

The immature cerebral cortex self-organizes into local neuronal clusters long before it is activated by patterned sensory inputs. In the cortical anlage of newborn mammals, neurons coassemble through electrical or chemical synapses either spontaneously or by activation of transmitter-gated receptors. The neuronal network and the cellular mechanisms underlying this cortical self-organization process during early development are not completely understood. Here we show in an intact in vitro preparation of the immature mouse cerebral cortex that neurons are functionally coupled in local clusters by means of propagating network oscillations in the beta frequency range. In the newborn mouse, this activity requires an intact subplate and is strongly synchronized within a cortical column by gap junctions. With the developmental disappearance of the subplate at the end of the first postnatal week, activation of NMDA (N-methyl-D-aspartate) receptors in the immature cortical network is essential to generate this columnar activity pattern. Our findings show that during a brief developmental period the cortical network switches from a subplate-driven, gap-junction-coupled syncytium to a synaptic network acting through NMDA receptors to generate synchronized oscillatory activity, which may function as an early functional template for the development of the cortical columnar architecture.     

Gap junction adhesion is necessary for radial migration in the neocortex

Radial glia, the neuronal stem cells of the embryonic cerebral cortex, reside deep within the developing brain and extend radial fibres to the pial surface, along which embryonic neurons migrate to reach the cortical plate. Here we show that the gap junction subunits connexin 26 (Cx26) and connexin 43 (Cx43) are expressed at the contact points between radial fibres and migrating neurons, and acute downregulation of Cx26 or Cx43 impairs the migration of neurons to the cortical plate. Unexpectedly, gap junctions do not mediate neuronal migration by acting in the classical manner to provide an aqueous channel for cell-cell communication. Instead, gap junctions provide dynamic adhesive contacts that interact with the internal cytoskeleton to enable leading process stabilization along radial fibres as well as the subsequent translocation of the nucleus. These results indicate that gap junction adhesions are necessary for glial-guided neuronal migration, raising the possibility that the adhesive properties of gap junctions may have an important role in other physiological processes and diseases associated with gap junction function.     

基于图论算法的脊髓损伤后大脑皮层运动区神经元网络分析

 脊髓损伤(SCI)后大脑皮层运动区神经元的功能重组对机体功能康复的影响仍然不为人知。脊髓损伤前后,对一只在跑步机上直立行走的恒河猴的大脑皮层运动区神经元信号进行记录,利用不同神经元动作电位序列间的相关系数建立神经元网络图。为了研究神经元活动模式的变化与功能康复之间的联系,利用图论算法计算了神经元网络图的全局效能指标和神经元脆弱性指标。结果显示,不同时期神经元活动模式的显著变化意味着运动区神经元的功能重组(神经可塑性)与脊髓损伤后猴子的功能康复状态紧密相关,且这种神经功能重组对于猴子步行功能的康复起了非常重要的积极作用。     

Local sleep in awake rats

In an awake state, neurons in the cerebral cortex fire irregularly and electroencephalogram (EEG) recordings display low-amplitude, high-frequency fluctuations. During sleep, neurons oscillate between 'on' periods, when they fire as in an awake brain, and 'off' periods, when they stop firing altogether and the EEG displays high-amplitude slow waves. However, what happens to neuronal firing after a long period of being awake is not known. Here we show that in freely behaving rats after a long period in an awake state, cortical neurons can go briefly 'offline' as in sleep, accompanied by slow waves in the local EEG. Neurons often go offline in one cortical area but not in another, and during these periods of 'local sleep', the incidence of which increases with the duration of the awake state, rats are active and display an 'awake' EEG. However, they are progressively impaired in a sugar pellet reaching task. Thus, although both the EEG and behaviour indicate wakefulness, local populations of neurons in the cortex may be falling asleep, with negative consequences for performance.     

Guarding the gateway to cortex with attention in visual thalamus

The massive visual input from the eye to the brain requires selective processing of some visual information at the expense of other information, a process referred to as visual attention. Increases in the responses of visual neurons with attention have been extensively studied along the visual processing streams in monkey cerebral cortex, from primary visual areas to parietal and frontal cortex. Here we show, by recording neurons in attending macaque monkeys (Macaca mulatta), that attention modulates visual signals before they even reach cortex by increasing responses of both magnocellular and parvocellular neurons in the first relay between retina and cortex, the lateral geniculate nucleus (LGN). At the same time, attention decreases neuronal responses in the adjacent thalamic reticular nucleus (TRN). Crick argued for such modulation of the LGN by observing that it is inhibited by the TRN, and suggested that "if the thalamus is the gateway to the cortex, the reticular complex might be described as the guardian of the gateway", a reciprocal relationship we now show to be more than just hypothesis. The reciprocal modulation in LGN and TRN appears only during the initial visual response, but the modulation of LGN reappears later in the response, suggesting separate early and late sources of attentional modulation in LGN.     

Functional localization and lateralization of human olfactory cortex.

Anatomical and physiological investigations in monkeys indicate that olfaction is subserved by several cortical regions. But the areas implicated in the human olfactory system have not been definitively identified by functional criteria. Behavioural evidence has suggested that laterally specialized mechanisms for odour processing may exist, but the neuroanatomical substrate remains unknown. We used positron emission tomography to study the cortical representation of human olfactory processing by comparing cerebral blood flow changes evoked during olfactory stimulation with those of a control task. We report here significant cerebral blood flow increases at the junction of the inferior frontal and temporal lobes bilaterally, corresponding to the piriform cortex, and unilaterally, in the right orbitofrontal cortex. The results complement and extend previous data implicating these regions in olfactory processing, and indicate that a functional asymmetry exists in the human brain favouring the right orbitofrontal area in olfaction.     

Cortical remodelling induced by activity of ventral tegmental dopamine neurons.

Representations of sensory stimuli in the cerebral cortex can undergo progressive remodelling according to the behavioural importance of the stimuli. The cortex receives widespread projections from dopamine neurons in the ventral tegmental area (VTA), which are activated by new stimuli or unpredicted rewards, and are believed to provide a reinforcement signal for such learning-related cortical reorganization. In the primary auditory cortex (AI) dopamine release has been observed during auditory learning that remodels the sound-frequency representations. Furthermore, dopamine modulates long-term potentiation, a putative cellular mechanism underlying plasticity. Here we show that stimulating the VTA together with an auditory stimulus of a particular tone increases the cortical area and selectivity of the neural responses to that sound stimulus in AI. Conversely, the AI representations of nearby sound frequencies are selectively decreased. Strong, sharply tuned responses to the paired tones also emerge in a second cortical area, whereas the same stimuli evoke only poor or non-selective responses in this second cortical field in naive animals. In addition, we found that strong long-range coherence of neuronal discharge emerges between AI and this secondary auditory cortical area.     

Functional imaging with cellular resolution reveals precise micro-architecture in visual cortex

Neurons in the cerebral cortex are organized into anatomical columns, with ensembles of cells arranged from the surface to the white matter. Within a column, neurons often share functional properties, such as selectivity for stimulus orientation; columns with distinct properties, such as different preferred orientations, tile the cortical surface in orderly patterns. This functional architecture was discovered with the relatively sparse sampling of microelectrode recordings. Optical imaging of membrane voltage or metabolic activity elucidated the overall geometry of functional maps, but is averaged over many cells (resolution >100 microm). Consequently, the purity of functional domains and the precision of the borders between them could not be resolved. Here, we labelled thousands of neurons of the visual cortex with a calcium-sensitive indicator in vivo. We then imaged the activity of neuronal populations at single-cell resolution with two-photon microscopy up to a depth of 400 microm. In rat primary visual cortex, neurons had robust orientation selectivity but there was no discernible local structure; neighbouring neurons often responded to different orientations. In area 18 of cat visual cortex, functional maps were organized at a fine scale. Neurons with opposite preferences for stimulus direction were segregated with extraordinary spatial precision in three dimensions, with columnar borders one to two cells wide. These results indicate that cortical maps can be built with single-cell precision.     

A functional role for vasoactive intestinal polypeptide in anterior cingulate cortex

Vasoactive intestinal polypeptide (VIP) is present in high concentrations in the cerebral cortex, where it is the putative neurotransmitter of a major intracortical neuronal system. Homogenates of cortical tissue contain high-affinity, specific binding sites for VIP as well as an adenylate cyclase system which is sensitive to this peptide. As with many of the other peptidergic systems which have been identified in the central nervous system (CNS), it has proved extremely difficult to elucidate the nature and extent of the functional role of VIP in specific brain areas. Here, using the quantitative autoradiographic 14C-deoxyglucose technique in rats to provide insight into functional processes, we describe the increases in glucose utilization which occur locally in anterior cingulate cortex following the unilateral injection of VIP (20 pmol) into this key brain area and, additionally, the focal alterations in glucose use in CNS regions having known neuronal connections with the injected region (for example, ipsilateral mediodorsal thalamus, ventral tegmental area, nucleus accumbens, caudate nucleus and contralateral cingulate cortex). These data provide evidence that VIP may modify the processing of afferent and efferent information within the anterior cingulate cortex in the conscious rat.     

Prostaglandins and the synergism between VIP and noradrenaline in the cerebral cortex

We have previously shown that vasoactive intestinal peptide (VIP) and noradrenaline (NA) interact synergistically to increase cyclic AMP levels in mouse cerebral cortical slices. The pharmacological mechanism of this synergism is the potentiation by NA, through alpha 1 adrenergic receptors, of the stimulatory effect of VIP on cAMP formation. A similar interaction has been confirmed in guinea pig cerebral cortex and in discrete nuclei of the rat hypothalamus. Furthermore VIP and NA interact synergistically to depress the spontaneous activity of identified neurons in rat neocortex. At the cellular level, this synergistic interaction suggests that VIP- and NA-containing neuronal systems may converge, at least in part, on the same target cells to increase cAMP levels in the cerebral cortex. At the molecular level, the interaction may occur at various steps in signal transduction, between receptors, intramembrane transduction processes or intracellular effector mechanisms. Here we report that the alpha 1-adrenergic potentiation of the increases in cAMP elicited by VIP involves the formation of arachidonic acid metabolites and is mimicked by prostglandins F2 alpha and E2.     

Functional specificity of local synaptic connections in neocortical networks

Neuronal connectivity is fundamental to information processing in the brain. Therefore, understanding the mechanisms of sensory processing requires uncovering how connection patterns between neurons relate to their function. On a coarse scale, long-range projections can preferentially link cortical regions with similar responses to sensory stimuli. But on the local scale, where dendrites and axons overlap substantially, the functional specificity of connections remains unknown. Here we determine synaptic connectivity between nearby layer 2/3 pyramidal neurons in vitro, the response properties of which were first characterized in mouse visual cortex in vivo. We found that connection probability was related to the similarity of visually driven neuronal activity. Neurons with the same preference for oriented stimuli connected at twice the rate of neurons with orthogonal orientation preferences. Neurons responding similarly to naturalistic stimuli formed connections at much higher rates than those with uncorrelated responses. Bidirectional synaptic connections were found more frequently between neuronal pairs with strongly correlated visual responses. Our results reveal the degree of functional specificity of local synaptic connections in the visual cortex, and point to the existence of fine-scale subnetworks dedicated to processing related sensory information.     

Top-down signal from prefrontal cortex in executive control of memory retrieval.

Knowledge or experience is voluntarily recalled from memory by reactivation of the neural representations in the cerebral association cortex. In inferior temporal cortex, which serves as the storehouse of visual long-term memory, activation of mnemonic engrams through electric stimulation results in imagery recall in humans, and neurons can be dynamically activated by the necessity for memory recall in monkeys. Neuropsychological studies and previous split-brain experiments predicted that prefrontal cortex exerts executive control upon inferior temporal cortex in memory retrieval; however, no neuronal correlate of this process has ever been detected. Here we show evidence of the top-down signal from prefrontal cortex. In the absence of bottom-up visual inputs, single inferior temporal neurons were activated by the top-down signal, which conveyed information on semantic categorization imposed by visual stimulus-stimulus association. Behavioural performance was severely impaired with loss of the top-down signal. Control experiments confirmed that the signal was transmitted not through a subcortical but through a fronto-temporal cortical pathway. Thus, feedback projections from prefrontal cortex to the posterior association cortex appear to serve the executive control of voluntary recall.     

Boosting slow oscillations during sleep potentiates memory

There is compelling evidence that sleep contributes to the long-term consolidation of new memories. This function of sleep has been linked to slow (<1 Hz) potential oscillations, which predominantly arise from the prefrontal neocortex and characterize slow wave sleep. However, oscillations in brain potentials are commonly considered to be mere epiphenomena that reflect synchronized activity arising from neuronal networks, which links the membrane and synaptic processes of these neurons in time. Whether brain potentials and their extracellular equivalent have any physiological meaning per se is unclear, but can easily be investigated by inducing the extracellular oscillating potential fields of interest. Here we show that inducing slow oscillation-like potential fields by transcranial application of oscillating potentials (0.75 Hz) during early nocturnal non-rapid-eye-movement sleep, that is, a period of emerging slow wave sleep, enhances the retention of hippocampus-dependent declarative memories in healthy humans. The slowly oscillating potential stimulation induced an immediate increase in slow wave sleep, endogenous cortical slow oscillations and slow spindle activity in the frontal cortex. Brain stimulation with oscillations at 5 Hz--another frequency band that normally predominates during rapid-eye-movement sleep--decreased slow oscillations and left declarative memory unchanged. Our findings indicate that endogenous slow potential oscillations have a causal role in the sleep-associated consolidation of memory, and that this role is enhanced by field effects in cortical extracellular space.     

Cortical representations of olfactory input by trans-synaptic tracing

In the mouse, each class of olfactory receptor neurons expressing a given odorant receptor has convergent axonal projections to two specific glomeruli in the olfactory bulb, thereby creating an odour map. However, it is unclear how this map is represented in the olfactory cortex. Here we combine rabies-virus-dependent retrograde mono-trans-synaptic labelling with genetics to control the location, number and type of 'starter' cortical neurons, from which we trace their presynaptic neurons. We find that individual cortical neurons receive input from multiple mitral cells representing broadly distributed glomeruli. Different cortical areas represent the olfactory bulb input differently. For example, the cortical amygdala preferentially receives dorsal olfactory bulb input, whereas the piriform cortex samples the whole olfactory bulb without obvious bias. These differences probably reflect different functions of these cortical areas in mediating innate odour preference or associative memory. The trans-synaptic labelling method described here should be widely applicable to mapping connections throughout the mouse nervous system.     

Global and fine information coded by single neurons in the temporal visual cortex.

When we see a person's face, we can easily recognize their species, individual identity and emotional state. How does the brain represent such complex information? A substantial number of neurons in the macaque temporal cortex respond to faces. However, the neuronal mechanisms underlying the processing of complex information are not yet clear. Here we recorded the activity of single neurons in the temporal cortex of macaque monkeys while presenting visual stimuli consisting of geometric shapes, and monkey and human faces with various expressions. Information theory was used to investigate how well the neuronal responses could categorize the stimuli. We found that single neurons conveyed two different scales of facial information in their firing patterns, starting at different latencies. Global information, categorizing stimuli as monkey faces, human faces or shapes, was conveyed in the earliest part of the responses. Fine information about identity or expression was conveyed later, beginning on average 51 ms after global information. We speculate that global information could be used as a 'header' to prepare destination areas for receiving more detailed information.     

Top-down gain control of the auditory space map by gaze control circuitry in the barn owl

High-level circuits in the brain that control the direction of gaze are intimately linked with the control of visual spatial attention. Immediately before an animal directs its gaze towards a stimulus, both psychophysical sensitivity to that visual stimulus and the responsiveness of high-order neurons in the cerebral cortex that represent the stimulus increase dramatically. Equivalent effects on behavioural sensitivity and neuronal responsiveness to visual stimuli result from focal electrical microstimulation of gaze control centres in monkeys. Whether the gaze control system modulates neuronal responsiveness in sensory modalities other than vision is unknown. Here we show that electrical microstimulation applied to gaze control circuitry in the forebrain of barn owls regulates the gain of midbrain auditory responses in an attention-like manner. When the forebrain circuit was activated, midbrain responses to auditory stimuli at the location encoded by the forebrain site were enhanced and spatial selectivity was sharpened. The same stimulation suppressed responses to auditory stimuli represented at other locations in the midbrain map. Such space-specific, top-down regulation of auditory responses by gaze control circuitry in the barn owl suggests that the central nervous system uses a common strategy for dynamically regulating sensory gain that applies across modalities, brain areas and classes of vertebrate species. This approach provides a path for discovering mechanisms that underlie top-down gain control in the central nervous system.