Pharmacological specialization of learned auditory responses in the inferior colliculus of the barn owl

Neural tuning for interaural time difference (ITD) in the optic tectum of the owl is calibrated by experience-dependent plasticity occurring in the external nucleus of the inferior colliculus (ICX). When juvenile owls are subjected to a sustained lateral displacement of the visual field by wearing prismatic spectacles, the ITD tuning of ICX neurons becomes systematically altered; ICX neurons acquire novel auditory responses, termed "learned responses," to ITD values outside their normal, pre-existing tuning range. In this study, we compared the glutamatergic pharmacology of learned responses with that of normal responses expressed by the same ICX neurons. Measurements were made in the ICX using iontophoretic application of glutamate receptor antagonists. We found that in early stages of ITD tuning adjustment, soon after learned responses had been induced by experience-dependent processes, the NMDA receptor antagonist D, L-2-amino-5-phosphonopentanoic acid (AP-5) preferentially blocked the expression of learned responses of many ICX neurons compared with that of normal responses of the same neurons. In contrast, the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) blocked learned and normal responses equally. After long periods of prism experience, preferential blockade of learned responses by AP-5 was no longer observed. These results indicate that NMDA receptors play a preferential role in the expression of learned responses soon after these responses have been induced by experience-dependent processes, whereas later in development or with additional prism experience (we cannot distinguish which), the differential NMDA receptor-mediated component of these responses disappears. This pharmacological progression resembles the changes that occur during maturation of glutamatergic synaptic currents during early development.     

Interactions between idiothetic cues and external landmarks in the control of place cells and head direction cells

Two types of neurons in the rat brain have been proposed to participate in spatial learning and navigation: place cells, which fire selectively in specific locations of an environment and which may constitute key elements of cognitive maps, and head direction cells, which fire selectively when the rat's head is pointed in a specific direction and which may serve as an internal compass to orient the cognitive map. The spatially and directionally selective properties of these cells arise from a complex interaction between input from external landmarks and from idiothetic cues; however, the exact nature of this interaction is poorly understood. To address this issue, directional information from visual landmarks was placed in direct conflict with directional information from idiothetic cues. When the mismatch between the two sources of information was small (45 degrees), the visual landmarks had robust control over the firing properties of place cells; when the mismatch was larger, however, the firing fields of the place cells were altered radically, and the hippocampus formed a new representation of the environment. Similarly, the visual cues had control over the firing properties of head direction cells when the mismatch was small (45 degrees), but the idiothetic input usually predominated over the visual landmarks when the mismatch was larger. Under some conditions, when the visual landmarks predominated after a large mismatch, there was always a delay before the visual cues exerted their control over head direction cells. These results support recent models proposing that prewired intrinsic connections enable idiothetic cues to serve as the primary drive on place cells and head direction cells, whereas modifiable extrinsic connections mediate a learned, secondary influence of visual landmarks.     

Cortical feedback improves discrimination between figure and background by V1, V2 and V3 neurons

A single visual stimulus activates neurons in many different cortical areas. A major challenge in cortical physiology is to understand how the neural activity in these numerous active zones leads to a unified percept of the visual scene. The anatomical basis for these interactions is the dense network of connections that link the visual areas. Within this network, feedforward connections transmit signals from lower-order areas such as V1 or V2 to higher-order areas. In addition, there is a dense web of feedback connections which, despite their anatomical prominence, remain functionally mysterious. Here we show, using reversible inactivation of a higher-order area (monkey area V5/MT), that feedback connections serve to amplify and focus activity of neurons in lower-order areas, and that they are important in the differentiation of figure from ground, particularly in the case of stimuli of low visibility. More specifically, we show that feedback connections facilitate responses to objects moving within the classical receptive field; enhance suppression evoked by background stimuli in the surrounding region; and have the strongest effects for stimuli of low salience.     

Fluorescence cross-correlation: a new concept for polymerase chain reaction

Infusion of sodium selenite to the occipital cortex of the rat was used for the specific tracing of zinc-rich pathways. Large numbers of labeled somata were found ipsilaterally in the visual, orbital and frontal cortices, and contralaterally in homotopic and heterotopic visual areas. Labeled neurons were also found ipsilaterally in the retrosplenial, parietal, sensory-motor, temporal and perirhinal cortex. In contrast to the cortico-cortical connections, ascending afferents to the visual cortex were not zinc-rich except for a few labeled neurons in the claustrum. Additional injections showed reciprocal zinc-rich connections between the visual cortex and the orbital and frontal cortices. The latter cortices also received ascending zinc-rich afferents from the claustrum. Selenite injections revealed the layered distribution and the morphology of these labeled neurons in the neocortex. Zinc-rich neurons were found in layers II-III, V and VI. However, none was found in layer IV. Zinc-rich somata appeared as pyramidal and inverted neurons. The contrasting chemical properties of cortical and subcortical visual afferents may account for the functional differences between these systems.     

Prefrontal connections of the parabelt auditory cortex in macaque monkeys

In the present study, we determined connections of three newly defined regions of auditory cortex with regions of the frontal lobe, and how two of these regions in the frontal lobe interconnect and connect to other portions of frontal cortex and the temporal lobe in macaque monkeys. We conceptualize auditory cortex as including a core of primary areas, a surrounding belt of auditory areas, a lateral parabelt of two divisions, and adjoining regions of temporal cortex with parabelt connections. Injections of several different fluorescent tracers and wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) were placed in caudal (CPB) and rostral (RPB) divisions of the parabelt, and in cortex of the superior temporal gyrus rostral to the parabelt with parabelt connections (STGr). Injections were also placed in two regions of the frontal lobe that were labeled by a parabelt injection in the same case. The results lead to several major conclusions. First, CPB injections label many neurons in dorsal prearcuate cortex in the region of the frontal eye field and neurons in dorsal prefrontal cortex of the principal sulcus, but few or no neurons in orbitofrontal cortex. Fine-grain label in these same regions as a result of a WGA-HRP injection suggests that the connections are reciprocal. Second, RPB injections label overlapping prearcuate and principal sulcus locations, as well as more rostral cortex of the principal sulcus, and several locations in orbitofrontal cortex. Third, STGr injections label locations in orbitofrontal cortex, some of which overlap those of RPB injections, but not prearcuate or principal sulcus locations. Fourth, injections in prearcuate and principal sulcus locations labeled by a CPB injection labeled neurons in CPB and RPB, with little involvement of the auditory belt and no involvement of the core. In addition, the results indicated that the two frontal lobe regions are densely interconnected. They also connect with largely separate regions of the frontal pole and more medial premotor and dorsal prefrontal cortex, but not with the extensive orbitofrontal region which has RPB and STGr connections. The results suggest that both RPB and CPB provide the major auditory connections with the region related to directing eye movements towards stimuli of interest, and the dorsal prefrontal cortex for working memory. Other auditory connections to these regions of the frontal lobe appear to be minor. RPB has connections with orbitofrontal cortex, important in psychosocial and emotional functions, while STGr primarily connects with orbital and polar prefrontal cortex.     

Establishment of patterned thalamocortical connections does not require nitric oxide synthase

Subplate neurons are early-generated neurons that project into the overlying neocortex and are required for the formation of ocular dominance columns. A subset of subplate neurons express nitric oxide synthase (NOS) and produce nitric oxide (NO), a neuronal messenger thought to be involved in adult hippocampal synaptic plasticity and also in the establishment of certain specific connections during visual system development. Here, we examine whether the NOS-containing subplate neurons are involved in ocular dominance column formation in the ferret visual system. Ocular dominance columns form in ferrets between postnatal day 35 (P35) and P60. NOS expression in the visual subplate is low at birth, increases to a maximum at the onset of ocular dominance column formation, and falls thereafter. Nevertheless, blockade of NOS with daily injections of nitroarginine from P14 to P56 fails to prevent the formation of ocular dominance columns, although NOS activity is reduced by >98%. To test further a requirement for NOS in the patterning of connections during CNS development, we examined the cortical barrels in the somatosensory system of mice carrying targeted disruptions of NOS that also received injections of nitroarginine; cortical barrels formed normally in these animals. In addition, barrel field plasticity induced by whisker ablation at birth was normal in nitroarginine-injected NOS knock-out mice. Thus, despite the dynamic regulation of NOS in subplate neurons, NO is unlikely to be essential for the patterning of thalamocortical connections either in visual or somatosensory systems.     

Differential signaling via the same axon of neocortical pyramidal neurons

The nature of information stemming from a single neuron and conveyed simultaneously to several hundred target neurons is not known. Triple and quadruple neuron recordings revealed that each synaptic connection established by neocortical pyramidal neurons is potentially unique. Specifically, synaptic connections onto the same morphological class differed in the numbers and dendritic locations of synaptic contacts, their absolute synaptic strengths, as well as their rates of synaptic depression and recovery from depression. The same axon of a pyramidal neuron innervating another pyramidal neuron and an interneuron mediated frequency-dependent depression and facilitation, respectively, during high frequency discharges of presynaptic action potentials, suggesting that the different natures of the target neurons underlie qualitative differences in synaptic properties. Facilitating-type synaptic connections established by three pyramidal neurons of the same class onto a single interneuron, were all qualitatively similar with a combination of facilitation and depression mechanisms. The time courses of facilitation and depression, however, differed for these convergent connections, suggesting that different pre-postsynaptic interactions underlie quantitative differences in synaptic properties. Mathematical analysis of the transfer functions of frequency-dependent synapses revealed supra-linear, linear, and sub-linear signaling regimes in which mixtures of presynaptic rates, integrals of rates, and derivatives of rates are transferred to targets depending on the precise values of the synaptic parameters and the history of presynaptic action potential activity. Heterogeneity of synaptic transfer functions therefore allows multiple synaptic representations of the same presynaptic action potential train and suggests that these synaptic representations are regulated in a complex manner. It is therefore proposed that differential signaling is a key mechanism in neocortical information processing, which can be regulated by selective synaptic modifications.     

Callosally projecting neurons in the macaque monkey V1/V2 border are enriched in nonphosphorylated neurofilament protein

Previous immunohistochemical studies combined with retrograde tracing in macaque monkeys have demonstrated that corticocortical projections can be differentiated by their content of neurofilament protein. The present study analyzed the distribution of nonphosphorylated neurofilament protein in callosally projecting neurons located at the V1/V2 border. All of the retrogradely labeled neurons were located in layer III at the V1/V2 border and at an immediately adjacent zone of area V2. A quantitative analysis showed that the vast majority (almost 95%) of these interhemispheric projection neurons contain neurofilament protein immunoreactivity. This observation differs from data obtained in other sets of callosal connections, including homotypical interhemispheric projections in the prefrontal, temporal, and parietal association cortices, that were found to contain uniformly low proportions of neurofilament protein-immunoreactive neurons. Comparably, highly variable proportions of neurofilament protein-containing neurons have been reported in intrahemispheric corticocortical pathways, including feedforward and feedback visual connections. These results indicate that neurofilament protein is a prominent neurochemical feature that identifies a particular population of interhemispheric projection neurons at the V1/V2 border and suggest that this biochemical attribute may be critical for the function of this subset of callosal neurons.     

Cytochrome-oxidase blobs and intrinsic horizontal connections of layer 2/3 pyramidal neurons in primate V1

Pyramidal neurons in superficial layers of cerebral cortex have extensive horizontal axons that provide a substrate for lateral interactions across cortical columns. These connections are believed to link functionally similar regions, as suggested by the observation that cytochrome-oxidase blobs in the monkey primary visual cortex (V1) are preferentially connected to blobs and interblobs to interblobs. To better understand the precise relationship between horizontal connections and blobs, we intracellularly labeled 20 layer 2/3 pyramidal neurons in tangential living brain slices from V1 of macaque monkeys. The locations of each cell body and the cell's synaptic boutons relative to blobs were quantitatively analyzed. We found evidence for two cell types located at characteristic distances from blob centers: (1) neurons lacking long-distance, clustered axons (somata 130-200 microm from blob centers) and (2) cells with clustered, long-distance axon collaterals (somata < 130 microm or >200 microm from blob centers). For all cells, synaptic boutons close to the cell body were located at similar distances from blob centers as the cell body. The majority of boutons from cells lacking distal axon clusters were close to their cell bodies. Cells located more than 200 microm from blob centers were in interblobs and had long-distance clustered axon collaterals selectively targeting distant interblob regions. Cells located less than 130 microm from blob centers were found within both blobs and interblobs, but many were close to traditionally defined borders. The distant synaptic boutons from these cells were generally located relatively near to blob centers, but the neurons closest to blob centers had synaptic boutons closer to blob centers than those farther away. There was not a sharp transition that would suggest specificity for blobs and interblobs as discrete, binary entities. Instead they appear to be extremes along a continuum. These observations have important implications for the function of lateral interactions within V1.     

Contextual cueing: implicit learning and memory of visual context guides spatial attention

Global context plays an important, but poorly understood, role in visual tasks. This study demonstrates that a robust memory for visual context exists to guide spatial attention. Global context was operationalized as the spatial layout of objects in visual search displays. Half of the configurations were repeated across blocks throughout the entire session, and targets appeared within consistent locations in these arrays. Targets appearing in learned configurations were detected more quickly. This newly discovered form of search facilitation is termed contextual cueing. Contextual cueing is driven by incidentally learned associations between spatial configurations (context) and target locations. This benefit was obtained despite chance performance for recognizing the configurations, suggesting that the memory for context was implicit. The results show how implicit learning and memory of visual context can guide spatial attention towards task-relevant aspects of a scene.     

Regenerating ganglion cell axons in the adult rat establish retinofugal topography and restore visual function

The mechanisms of neuronal network response to axotomy are poorly understood. In one of the favoured models used to study the fate of injured neurons in the adult rat visual system, appreciable numbers of retinal neurons survive optic nerve injury under conditions of microglia-targeted neuroprotection. Rescued neurons can regenerate their axons and become target-dependently stabilised after reconnection with their natural visual centres by means of a peripheral nerve graft, which, in addition to guidance, actively supports axonal growth. The mechanisms that control regenerative axonal growth and resynaptogenesis include coordinated cell-cell interactions between growing neurites and target cells in order to establish a meaningful reconnectivity. Here the function of the regenerating visual circuitry was first studied by monitoring the ability of animals to discriminate spatial patterns, and second by recording visual evoked cortical potentials (VEPs) in the same animals. These functions were correlated with neuroanatomical studies of the retinotopic organisation of regenerating axons. To achieve these goals, adult rats were behaviourally trained in a Y-maze to discriminate between vertical and horizontal stripes. Both optic nerves were transected, and the regenerating axons of one optic nerve were guided into the area of optic tract with a peripheral nerve graft according to the protocols of neuroprotection and simultaneous grafting, in order to enable large numbers of axons to reinnervate the major visual targets in the midbrain and thalamus. Postoperative testing of the animals showed a marked improvement of visual perception and behaviour. The VEPs of the same animals were measurable indicating a restoration of the visual circuitry including the ascending corticopedal connections. Neuroanatomical assessment of the fibre topography within the graft and the area of termination revealed a rough topographic organisation that may account for restoration of the function. These results suggest that interrupted central pathways can be functionally reconnected by providing a neuroprotective environment in combination with peripheral nerve grafts to bypass lesions.     

Intrinsic circuitry in the deep layers of the cat superior colliculus

The mammalian superior colliculus is involved in the transformation of sensory signals into orienting behaviors. Sensory and motor signals are integrated in the colliculus to produce movements of the eyes, head, and neck. While there is a considerable amount of information available on the afferent and efferent connections of the colliculus, almost nothing is known about its intrinsic circuitry, particularly that of its deepest layers. It is likely that intrinsic connections in these deeper layers of the colliculus participate in the sensory-motor transformations leading to orienting movements. In this study, we used the neuroanatomical tracer biocytin to label small groups of neurons in the deeper layers of the cat superior colliculus and examine the distribution of their axons and terminals. We found a broadly distributed network of intrinsic projections throughout the deep layers of the superior colliculus. While the majority of terminals were found in a 1-2 mm radius around the injection site, labeled terminals were found throughout the deep layers of the colliculus up to 5 mm from the injection site. In addition, these injections sometimes labeled terminals in the superficial tectum. Extensive projections were demonstrated by the more superficial injections, but few terminals were found when injections were confined to the deepest layers of the colliculus. There was no evidence of anisotropy in the distribution of terminals from injections made at different rostrocaudal or mediolateral locations; neurons located in any one region in the colliculus could potentially influence any other region. This network of intrinsic connections in the cat superior colliculus could provide a means for deeper-layer efferent neurons to associate, and to modulate or coordinate their output. Interneurons could also provide a substrate for mutual inhibition between neurons at the rostral pole of the colliculus that are active during fixation, and more caudally located neurons whose activity is associated with saccadic eye movements.     

Integration of local inputs in visual cortex

In mammalian visual cortex, local connections are ubiquitous, extensively linking adjacent neurons of all types. In this study, optical maps of intrinsic signals and responses from single neurons were obtained from the same region of cat visual cortex while the effectiveness of the local cortical circuitry was altered by focally disinhibiting neurons within a column of known orientation preference. Maps of intrinsic signals indicated that local connections provide strong and functional subthreshold inputs to neighboring columns of other orientation preferences, altering the observed orientation preference to that of the disinhibited column. However, measuring the suprathreshold response using single-cell recordings revealed only mild changes of preferred orientation over the affected region. Because strongly tuned subthreshold inputs from cortex only marginally affect the tuning of a cortical cell's output, it is concluded that local cortical inputs are integrated weakly compared to geniculate inputs. Such circuitry potentially allows for the normalization of responses across a wide range of input activity through local averaging.     

Development of orientation preference maps in area 18 of kitten visual cortex

We investigated the development of orientation preference maps in the visual cortex of kittens by repeated optical imaging from the same animal. Orientation maps became detectable for the first time around postnatal day (P) 17 and improved continuously in strength unitl P30, the time at which their appearance became adultlike. During this developmental period the overall geometry of the maps remained unchanged, suggesting that the layout of the orientation map is specified prior to P17. Hence, before the visual cortex becomes susceptible to experience-dependent modifications its functional architecture is largely specified. This suggests that the initial development and layout of orientation preference maps are determined by intrinsic processes that are independent of visual experience. This conclusion is further supported by the result that orientation maps were well expressed at P24 in binocularly deprived kittens. Because the appearance of the first orientation-selective neurons and the subsequent development of orientation preference maps correlated well with the time course of the expression and refinement of clustered horizontal connections, we propose that these connections might contribute to the specification of orientation preference maps.     

Early monaural occlusion alters the neural map of interaural level differences in the inferior colliculus of the barn owl

Monaural occlusion during early life causes adaptive changes in the tuning of units in the owl's optic tectum to interaural level differences (ILD) that tend to align the auditory with the visual map of space. We investigated whether these changes could be due to experience-dependent plasticity occurring in the auditory pathway prior to the optic tectum. Units were recorded in the external nucleus of the inferior colliculus (ICx), which is a major source of auditory input to the optic tectum. The tuning of ICx units to ILD was measured in normal barn owls and in barn owls raised with one ear occluded. ILD tuning at each recording site was measured with dichotic noise bursts, presented at a constant average binaural level, 20 dB above threshold. The best ILD at each site was defined as the midpoint of the range of ILD values which elicited more than 50% of the maximum response. A physiological map of ILD was found in the ICx of normal owls: best ILDs changed systematically from right-ear-greater to left-ear-greater as the electrode progressed from dorsal to ventral. Best ILDs ranged from 13 dB right-ear-greater to 15 dB left-ear-greater and progressed at an average rate of 12 dB/mm. The representations of ILD were similar on both sides of the brain. In the ICx of owls raised with one ear occluded, the map of ILD was shifted in the adaptive direction: ILD tuning was shifted towards values favoring the non-occluded ear (the direction that would restore a normal space map). The average magnitude of the shift was on the order of 8-10 dB in each of 4 owls. In one owl, the mean shift in ILD tuning was almost identical on both sides of the brain. In another owl, the mean shift was much larger on the side ipsilateral to the occlusion than on the contralateral side. In both cases, the mean shifts measured in each ICx were comparable to the mean shifts measured in the optic tectum on the same sides of the brain. Thus, the adjustments in ILD tuning that have been observed in the optic tectum in response to monaural occlusion are almost entirely due to adaptive mechanisms that operate at or before the level of the ICx.     

The influence of stimulus properties on multisensory processing in the awake primate superior colliculus.

Evaluated the influence of physical properties of sensory stimuli (visual intensity, direction, and velocity; auditory intensity and location) on sensory activity and multisensory integration of superior colliculus (SC) neurons in awake, behaving primates. Two male monkeys were trained to fixate a central visual fixation point while visual and/or auditory stimuli were presented in the periphery. Visual stimuli were always presented within the contralateral receptive field of the neuron whereas auditory stimuli were presented at either ipsi- or contralateral locations. 66 of the 84 SC neurons responsive to these sensory stimuli had stronger responses when the visual and auditory stimuli were combined at contralateral locations than when the auditory stimulus was located on the ipsilateral side. This trend was significant across the population of auditory-responsive neurons. In addition, 31 SC neurons were presented a battery of tests in which the quality of one stimulus of a pair was systematically manipulated. Eight of these neurons showed preferential responses to stimuli with specific physical properties, and these preferences were not significantly altered when multisensory stimulus combinations were presented. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Exploring brain circuitry with neurotropic viruses: new horizons in neuroanatomy

There have been substantial advances in methods for defining connections among neurons over the past quarter century. However, most tracers have been limited in their ability to define populations of functionally related neurons that contribute to a multisynaptic circuit because they are not transported across synapses. As a result, the large body of literature that has employed these tracers has established regional associations between regions that must be further explored with electron microscopy and electrophysiological methods to define the synaptic relations among constituent neurons. Recently, neurotropic alpha herpesviruses have been used to visualize ensembles of neurons that contribute to polysynaptic networks. These pathogens invade permissive cells, replicate, and pass transynaptically to infect other neurons. In effect, the viruses become self-amplifying tracers whose natural tropism and invasiveness define populations of functionally related neurons. The recent increase in the use of this experimental approach has emerged from advances in our understanding of the life cycle of these viruses and the resulting evidence in support of specific transynaptic passage of progeny virus rather than infection by lytic release into the extracellular space. This article reviews the advances that have made this a viable experimental approach and considers ways in which this method has been creatively used to illuminate aspects of nervous system circuit organization that could not be defined with conventional tracers.     

Peripheral target specification of synaptic connectivity of muscle spindle sensory neurons with spinal motoneurons

The source of environmental cues determining the central connections of muscle sensory neurons was investigated by manipulating chick embryos so that sensory neurons supplied a duplicate set of dorsal thigh muscles. These neurons projected out ventral nerve pathways and along motor axons that normally project to ventral muscles but their ultimate target tissue was the duplicate set of dorsal muscles. The central connections of these sensory neurons to motoneurons supplying normal dorsal muscles were then determined with intracellular recordings in isolated spinal cord preparations. Sensory neurons supplying individual duplicate dorsal muscles made the same connections as those supplying the corresponding normal dorsal muscles; the pattern of these connections was different than that made by afferents supplying ventral muscles. Sensory neurons thus made synaptic connections appropriate for their target muscle rather than for their more proximal ventral environment. These findings suggest that the target muscle is the source of cues that determine the central connections of the sensory neurons projecting to it. Motoneurons forced to innervate novel muscle received many of the same sensory inputs they would normally receive, suggesting that motoneurons are less influenced by their target tissue than sensory neurons.     

Roger Sperry and his chemoaffinity hypothesis

In the early 1940s, Roger Sperry performed a series of insightful experiments on the visual system of lower vertebrates that led him to draw two important conclusions: When optic fibers were severed, the regenerating fibers grew back to their original loci in the midbrain tectum to re-establish a topographical set of connections; and the re-establishment of these orderly connections underlay the orderly behavior of the animal. From these conclusions, he inferred that each optic fiber and each tectal neuron possessed cytochemical labels that uniquely denoted their neuronal type and position and that optic fibers could utilize these labels to selectively navigate to their matching target cell. This inference was subsequently formulated into a general explanation of how neurons form ordered interconnections during development and became known as the chemoaffinity hypothesis. The origins of this hypothesis, the controversies that surrounded it for several decades and its eventual acceptance, are discussed in this article.