Search

The 3α-hydroxy,5α-reduced pregnane steroids, allopregnanolone and allotetrahydrodeoxycorticosterone, are the most potent endogenous positive modulators of GABAA receptor-mediated inhibition. This study presents the first immunohistochemical examination of the cellular distribution of 3α-hydroxy,5α-reduced pregnane steroids across the brain. We found a widespread distribution in the adult rat, with dense immunolabelling in the olfactory bulb, striatum and cerebral cortex, and lower density labelling in the brainstem reticular formation. In general terms, this distribution accords with the regional concentrations of 3α-hydroxy,5α-reduced steroids determined, in other laboratories, by brain region sampling and either gas chromatography-mass fragmentography or radioimmunoassay. However, immunohistochemistry allowed for a more detailed examination of regional distribution and cellular specificity. All immunoreactivity was confined to the cell bodies and thick dendrites of neurones; no identifiable glia were labelled. In most brain areas, the location and morphology of labelled cells identified them as excitatory neurones. In addition, cell populations known to be projecting GABAergic neurones (e.g. cerebellar Purkinje cells) were immunoreactive, whereas local inhibitory neurones generally were not. The cellular distribution of 3α-hydroxy,5α-reduced steroids suggests that sensory, motor, limbic and homeostatic systems can be influenced by neurosteroids at multiple stages of processing.

Studies of the effects of peripheral and central lesions, perceptual learning and neurochemical modification on the sensory representations in cortex have had a dramatic effect in alerting neuroscientists and therapists to the reorganizational capacity of the adult brain. An intriguing aspect of some of these investigations, such as partial peripheral denervation, is the short-term expression of these changes. Indeed, in visual cortex, auditory cortex and somatosensory cortex loss of input from a region of the peripheral receptor epithelium (retinal, basilar and cutaneous, respectively) induces rapid expression of ectopic, or expanded, receptive fields of affected neurons and reorganization of topographic maps to fill in the representation of the denervated area. The extent of these changes can, in some cases, match the maximal extents demonstrated with chronic manipulations. The rapidity, and reversibility, of the effects rules out many possible explanations which involve synaptic plasticity and points to a capacity for representational plasticity being inherent in the circuitry of a topographic pathway. Consequently, topographic representations must be considered as manifestations of physiological interaction rather than as anatomical constructs. Interference with this interaction can produce an unmasking of previously inhibited responsiveness. Consideration of the nature of masking inhibition which is consistent with the precision and order of a topographic representation and which has a capacity for rapid plasticity requires, in addition to stimulus-driven inhibition, a source of tonic input from the periphery. Such input, acting locally to provide tonic inhibition, has been directly demonstrated in the somatosensory system and is consistent with results obtained in auditory and visual systems.

presented at The Physiological Society Scientific Meeting, University of Leeds, 2002

Circumscribed laser lesions were made in the nasal retinae of one eye in adolescent cats. Ten to sixteen months later, about 80 % of single neurones recorded in the lesion projection zone (LPZ) of contralateral area 18 (parastriate cortex, area V2) were binocular but when stimulated via the lesioned eye had ectopic discharge fields (displaced to normal retina in the vicinity of the lesion). Although the clear majority of binocular cells recorded from the LPZ responded with higher peak discharge rates to stimuli presented via the non-lesioned eye, the orientation and direction selectivities as well as preferred and upper cut-off velocities for stimuli presented through either eye were very similar. Furthermore, the sizes of the ectopic discharge fields of binocular cells recorded from the LPZ were not significantly different from those of their counterparts plotted via the non-lesioned eye. Thus, monocular retinal lesions performed in adolescent cats induce topographic reorganization in the LPZ of area 18. Although a similar reorganization occurs in area 17 (striate cortex, area V1) of cats in which monocular retinal lesions were made either in adulthood or adolescence, in view of the very different velocity response profiles of ectopic discharge fields in areas 17 and those in area 18, it appears that ectopic discharge fields in area 17 are largely independent of excitatory feedback input from area 18.

It is now clear, from a large number of studies, that disruption of a subset of the inputs to the sensory representations in cortex of adult manunals induces a rapid unmasking of larger neuronal receptive fields and an increased neuronal responsiveness. Within the somatosensory cortex, such demonstrations indicate that a capacity for short-term plasticity results from the unmasking of normally unexpressed inputs to a cortical locus. Despite the clear demonstration of such unmasking, an explanation for how this occurs is not immediately apparent. Aside from the studies directly demonstrating short-term plasticity, there have been anatomical (Landry and Deschenes, 1981; Garraghty and Sur, 1990), physiological (Snow et aI., 1988) and pharmacological (e.g. Dykes et al., 1984) demonstrations of cortical afferents that are not normally expressed as part of neural receptive fields. The rapid unmasking phenomena indicate that these inputs are inherently viable and thus must normally be actively suppressed. The only candidate source for an inhibition which can account for this suppression is that produced by the GABAergic interneurons located within a given cortical area. This short review will examine the implications that studies of short-term plasticity require for the nature of that inhibition, and the limitations of the capacity for plasticity that is dependent upon these normally unexpressed inputs.

We review the work of others in which the effects of circumscribed, topographically corresponding binocular retinal lesions on the topographic organization of the visual cortex revealed that there is a substantial degree of topographical plasticity in the primary visual cortices of adult cats and macaque monkeys. Despite the evidence indicating that the reorganization of the topographic map in primary visual cortices of adult cats and macaques related to the input from one eye could be suppressed for a long time by inputs related to the other eye, we observed a substantial degree of topographical plasticity in the primary visual cortices of adult cats in which we have made circumscribed monocular retinal lesions. Overall, in both binocularly and monocularly lesioned adult animals, most cells recorded in the cortical projection zone of the retinal lesion (LPZ), several hours, several weeks or several months after placement of the lesions exhibited 'ectopic' excitatory visual receptive fields (RFs) which were displaced to the normal retina in the immediate vicinity of the lesion. The presence of ectopic RFs in cells recorded in the cortical LPZ, combined with the presence of normal cortical representation of the part of the retina in the vicinity of the lesion, indicate a clear expansion of the cortical representation of the part of the retina surrounding the lesion. When stimulated via the ectopic RFs, cortical cells exhibited normal orientation tuning and in the case of animals with monocular lesions, the orientation tuning of binocular cells when stimulated via ectopic RFs appeared to be very similar to that when the cells were stimulated via the RFs in the normal, unlesioned eye. In both binocularly and monocularly lesioned animals, the responses evoked by optimal visual stimuli from the ectopic RFs were substantially weaker than those evoked from their normal counterparts. Similarly, upper velocity limits were significantly lower when visual stimuli were presente

1. In eight adult cats intense, sharply circumscribed, monocular laser lesions were used to remove all cellular layers of the retina. The extents of the retinal lesions were subsequently confirmed with counts of α-ganglion cells in retinal whole mounts; in some cases these revealed radial segmental degeneration of ganglion cells distal to the lesion. 2. Two to 24 weeks later, area 17 (striate cortex; V1) was studied electrophysiologically in a standard anaesthetized, paralysed (artificially respired) preparation. Recording singleor multineurone activity revealed extensive topographical reorganization within the lesion projection zone (LPZ). 3. Thus, with stimulation of the lesioned eye, about 75% of single neurones in the LPZ had ‘ectopic’ visual discharge fields which were displaced to normal retina in the immediate vicinity of the lesion. 4. The sizes of the ectopic discharge fields were not significantly different from the sizes of the normal discharge fields. Furthermore, binocular cells recorded from the LPZ, when stimulated via their ectopic receptive fields, exhibited orientation tuning and preferred stimulus velocities which were indistinguishable from those found when the cells were stimulated via the normal eye. 5. However, the responses to stimuli presented via ectopic discharge fields were generally weaker (lower peak discharge rates) than those to presentations via normal discharge fields, and were characterized by a lowerthannormal upper velocity limit. 6. Overall, the properties of the ectopic receptive fields indicate that cortical mechanisms rather than a retinal ‘periphery’ effect underlie the topographic reorganization of area 17 following monocular retinal lesions.

presented at the Physiological Society Meeting, Aberdeen, 2000

The primary sensory fields in cortex encode topographical representations of their peripheral epithelium (visual: retina; somatosensory: body surface; auditory: cochlear place or frequency) in which responsive neurons at a given locus or throughout a column have similar receptive fields, These representations provide useful model systems for the study of functional neuronal plasticity since they present an inbuilt scale upon which any changes can be measured. In the developing mammal, these representations have been shown to be capable of a remarkable degree of plasticity by virtue of the reorganization of the basic topography which follows from a changed peripheral input (Kelahan et aI., 1981; Spinelli and Jensen, 1979; Waite. 1984; Wall and Cusick, 1986) or from manipulation of central pathways (Roe et al 1990), Plasticity has also been demonstrated in the sensory cortex of adults where the removal of a restricted region of primary afferents can lead to the affected area of cortex gaining sensitivity to other regions (visual: Gilbert and Wiesel, 1992; Kaas et al 1990; Schmid et al 1995; 1996; auditory: Rajan et al 1993; Robertson and Irvine, 1989; somatosensory: see below). However, such changes in the organization of adult cortex must be considered fundamentally different in nature from those in neonates where there is a critical period for plasticity (Hubel and Wiesel, 1970; Wall, 1988). In the developing nervous system there are bases for mutability of the pattern of projections through disruption of the processes of initial connections, trimming of exuberant projections (e,g, Wall and Cusick, 1986) or alterations to the normal patterns of segregation of inputs (e.g. LeVay et al 1981). Such mechanisms of plasticity are not available in the adult brain where the connections are considered to be stable - although it does appear that some deprivation conditions may extend the developmental critical period (Daw et al 1992; Moore, 1993; Smith et al 1978), Neverthele

The technique of intracellular injection in fixed, flattened slices was used to study neuronal composition and morphology in the postero-medial barrel subfield (PMBSF) and the antero-lateral barrel subfield (ALBSF) in layer IV of rat cortex, The PMBSF and the ALBSF contain the cortical representation of the mystacial and rostral snout vibrissae respectively. Neuronal composition differed between the PMBSF and the ALBSF. Modified pyramidal cells were the most numerous neuronal type in the PMBSF (73.1%), whereas spiny multipolar (stellate) neurons were the most numerous type in the ALBSF (40.9%). Tangential dendritic field areas of modified pyramidal cells and spiny multipolar cells in the barrels of the two barrel subfields were compared, Dendritic field areas of spiny multipolar neurons located in the barrels of the PMBSF and the ALBSF were similar (mean +/- SD; 2.44 +/- 1.83 x 104 and 2.88 +/- 1.47 x 104 μm2 respectively). Likewise, there was no significant difference in 'basal' dendritic field area of modified pyramidal neurons located in the barrels of the two different barrel subfields (4.63 +/- 1.96 x 104 and 4.45 +/- 1.81 x 104 μm2 for PMBSF and ALBSF respectively). The mean cross-sectional area of PMBSF barrels (20.5 +/- 5.69 x 104 μm2) in which neurons were injected was approximately seven times larger than that of the ALBSF (2.94 +/- 1.46 x 104 μm2). Thus, on average, the dendritic territories of these two neuronal classes sample a larger proportion of the cross-sectional area of the barrels in the ALBSF than in the PMBSE We conclude that the close relationship between basal dendritic field area of supragranular pyramidal neurons and module size, reported in studies of other sensory areas, is not evident in all barrel subfields of the rat.

Several studies of auditory cortex have examined the competitive inhibition that can occur when appropriate sounds are presented to each ear. However, most cortical neurons also show both excitation and inhibition in response to presentation of stimuli at one ear alone. The extent of such inhibition has not been described. Forward masking, in which a variable masking stimulus was followed by a fixed probe stimulus (within the excitatory response area), was used to examine the extent of monaural inhibition for neurons in primary auditory cortex of anesthetized cats (barbiturate or barbiturate-ketamine). Both the masking and probe stimuli were 50-ms tone pips presented to the contralateral ear. Most cortical neurons showed significant forward masking at delays beyond which masking effects in the auditory nerve are relatively small compared with those seen in cortical neurons. Analysis was primarily concerned with such components. Standard rate-level functions were also obtained and were examined for nonmonotonicity, an indication of level-dependent monaural inhibition. 2. Consistent with previous reports, a wide range of frequency tuning properties (excitatory response area shapes) was found in cortical neurons. This was matched by a wide range of forward-masking-derived inhibitory response areas. At the most basic level of analysis, these were classified according to the presence of lateral inhibition, i.e., where a probe tone at a neuron's characteristic frequency was masked by tones outside the limits of the excitatory response area. Lateral inhibition was a property of 38% of the sampled neurons. Such neurons represented 77% of those with nonmonotonic rate-level functions, indicating a strong correlation between the two indexes of monaural inhibition; however, the shapes of forward masking inhibitory response areas did not usually correspond with those required to account for the "tuning" of a neuron. In addition, it was found that level-dependent inhibition was n

presented at The Association for Research in Vision and Ophthalmology Annual Meeting. Sarasota, Florida, May 1-6, 1994

The tonotopicity of the cat's primary auditory cortex (AI) is thought to provide the framework for frequency-specific processing in that field. This study was designed to assess this postulate by examining the spatial distribution of neurons within AI that are activated by a single tonal frequency delivered to the contralateral ear. Distributions obtained at each of several stimulus levels were then compared to assess the influence of stimulus amplitude on the spatial representation of a given stimulus frequency in AI. Data were obtained from 308 single units in AI of four adult, barbiturate-anesthetized cats, using extracellular recording methods. Stimuli were 40-ms tone pulses presented through calibrated, sealed stimulating systems. In each animal, the CF (stimulus frequency to which the unit is most sensitive), threshold at CF, response/level function at CF, and binaural interactions were determined for isolated neurons (usually one per track) in 60-90 electrode tracks. For each unit, regardless of its CF, responses to 40 repetitions of contralateral tones of a single frequency, presented at each of four or five sound pressure levels (SPLs) in the range from 10 to 80 dB were obtained. Different test frequencies were used in each of four cats (1.6, 8.0, 11.0, and 16.0 kHz). For tones of each SPL, we generated maps of the response rates across the cortical surface. These maps were then superimposed on the more traditional maps of threshold CF. All units whose CF was equal to the test frequency could be driven at some SPL, given an appropriate monaural or binaural configuration of the stimulus. There was a clear spatial segregation of neurons according to the shapes of their CF tone response/level functions. Patches of cortex, often occupying more than 2 mm(2), seemed to contain only monotonic or only nonmonotonic units. In three cortices, a patch of nonmonotonic cells was bounded ventrally by a patch of monotonic cells, and in one of these cases, a second patch of

The response areas (frequency by intensity) of single neurons in primary auditory cortex of anesthetized cats were studied before and after temporary threshold shifts in cochlear sensitivity induced by an intense pure tone. Cochlear temporary threshold shift was monitored through the threshold of the gross auditory nerve compound action potential and in most cases involved a notch-like loss centered at the characteristic frequency of the unit under study. Only two neurons showed changes in response area that mirrored the changes at the auditory periphery. Most neurons (14) showed more complex changes involving both expansion and contraction of response areas. Expansion of response areas was indicated by lower thresholds at some frequencies and by the emergence of sensitivity to previously ineffective frequencies. A change was classified as contraction when the response area after the intense-tone exposure was smaller than would be expected by applying the profile of the temporary threshold shift to the initial response area. Contraction of both upper (high intensity) and lower boundaries of response areas was found; in the most extreme cases, neurons were totally unresponsive after the intense-tone exposure.

1. Acute effects of permanent and temporary denervation of the flying fox thumb were examined to test the hypothesis that a large area of skin around the cutaneous receptive field of multiunits (MRF) at a locus in primary somatosensory cortex (SI) supplies viable inputs which can be rapidly unmasked by interruption of the dominant input from the area of the MRF. 2. The immediate effect of amputation of the thumb at loci where the original receptive field was entirely removed was to produce large MRFs on adjacent body areas (wrist, forearm, prowing, and finger membranes). Greatly expanded MRFs were also produced when amputation removed only part of the original MRF at a cortical locus. 3. The probable source of input to account for the new receptive fields is the extensive arborization of ascending projections within the somatosensory pathway, which supply a cortical locus with a potential input from a far larger area than is represented in its normal receptive field. The rapidity with which new or expanded fields are seen following denervation indicates that the normally unexpressed inputs around a receptive field are not only potential inputs but are inherently viable. Hence the most likely explanation for the results of this study is that the effect of the denervation is to disrupt an inhibitory influence that normally has the role of shaping the receptive field. 4. Temporary anesthesia of all or part of a MRF produced similar initial effects to amputation. When responsiveness returned to the locally anesthetized area (after 10-30 min), an expanded MRF persisted for a short time after which the boundaries of the MRF shrank. This rapid reversal suggests that a mechanistic rather than a plastic change is the basis for the acute effect of a small denervation on SI.

The short-term effect of total or partial single-digit denervation on receptive fields (Rds) of neurons in somatosensory cortex (area 3b) was examined in five macaque monkeys. In two animals, after denervation by amputation, it was found that electrode positions that initially recorded neurons with Rds on the amputated digit had new Rds extending from the wound. Often the new fields were on adjacent digits. Neurons with initial Rds that were partially amputated, or in some cases close to but not on the amputated digit, showed considerable expansion of the remaining RF. In three monkeys local anesthesia was used to provide a temporary denervation. In these experiments electrodes were placed in equivalent positions in both cortices. The effect on cortex contralateral to the denervation was similar to that seen with amputation. However, after esthesia returned to the digit, the expanded Rds contracted. In cortex ipsilateral to the denervation, Rds were on the opposite unaffected hand. These also rapidly expanded and then contracted, with the same time course as their counterparts in cortex contralateral to the denervation. Because of the rapidity of the expansion and its temporary nature with short-term denervation, the basis of the effect is probably an unmasking of existing but normally unexpressed connections, which are normally inhibited by the intact output from the denervated area. The wide arborization fields of thalamocortical afferents provide a potential source for the unmasked sensitivity. A mechanism for the inhibition that normally suppresses the expression of large Rds is not readily apparent. However, work in other species suggests that peripheral C fibers provide the primary source of input to central inhibitory circuits.

The responses to changes in stimulus azimuth of 204 neurons in the inferior colliculus of the cat with best frequencies of less than 3 kHz were studied. Three main unit classes were identified: omnidirectional units uninfluenced by speaker azimuth (39%); multipeaked units with several azimuthal regions at which peak firing occurred (9%); and azimuth-selective units that showed clear preferences for a discrete range of sound-source azimuths (52%). Alterations in stimulus intensity produced little change in the shapes of profiles relating firing rate to stimulus azimuth (azimuth functions), but the peaks of these functions could shift by up to 20 degrees. Similar observations were made for a small sample of units, each of which was examined with a variety of stimulus frequencies. The pinnae were removed bilaterally in 11 cats, and azimuth functions for 35 units were measured both binaurally and with the ipsilateral or contralateral ear occluded. Evidence was found for facilitative or suppressive interactions, as a function of stimulus azimuth, between monaural inputs. The sharpness of an azimuth function was expressed by the half-width of the function, i.e., the number of degrees of azimuth between the peak of the function and the point at which 50% of maximum firing occurred on the medial side of the peak. When half-widths were plotted as a function of best frequency, it was found that the sharpest azimuth functions occurred for units with best frequencies between 1.1 and 1.5 kHz. Most units in the lowest two octaves (0.1-0.4 kHz) or having best frequencies between 2 and 3 kHz were omnidirectional. The relationship between half-width and the azimuth at which peak firing occurred (best azimuth) revealed that a range of best azimuths between 10 and 40 degrees contralateral contained the sharpest azimuth functions. When best frequency was plotted against best azimuth, it was observed that the majority of units (93%) had best azimuths in the contralateral hemifield. For

1. Extracellular responses to auditory stimuli of single units in the principal division of the medial geniculate body were examined. Two distinct areas were identified on the basis of these responses, These positions correspond to the dorsocaudal (DC) and ventral (MGV) divisions of the principal division, as differentiated cytoarchitecturally. 2. Within MGV, the vast majority of units discharged transiently to the onset of the stimuli with a short latency. These units were also highly frequency specific, having sharp threshold tuning curves. In contrast, the majority of DC units were broadly tuned, responded at a long latency, and often habituated quickly to repetitive stimulation. 3. A small subset of DC units responded similarly to MGV units having sharp tuning curves and exhibiting short latencies to tonal stimuli. Unlike MGV, there was no tonotopic organization within DC. 4. Two separate tonotopically organized regions were found in MGV corresponding to the differentiation of this region into two separate but adjacent laminated nuclei. The tonotopic organization in three dimensions of pars lateralis (PL) revealed low frequencies ventrocaudolaterally with higher frequencies being added progressively dorsorostromedially. The frequency organization within pars ovoidea (OV) was not so easily discernible. However, penetrations in a dorsocaudal to ventrorostral orientation encountered an abrupt change from low to high frequencies at the presumed PL-OV border, followed by an increasing sequence of best frequencies within OV. 5. The differences in auditory response characteristics between MGV and IX are discussed in relation to the known anatomy and connections of the cat medial geniculate body.

Two ordered representations of the body surface, S-I and S-II, have been described on the cortical surface of the brains of a variety of mammals; additional separate topographical maps have been found in the somatosensory cortex of the cat and monkey. Except for minor variations in the placement of the body parts, the basic somatotopy of the maps is remarkably consistent across species. As the reasons for this consistency and the minor variations are unclear, we examined the somatotopy of the bat, whose body plan has been modified extensively so that the forelimb can be used for flight. We report here that in both S-I and S-II of the grey-headed flying fox, not only is the representation of the distal forelimb displaced from its usual position on the map, but the digits are directed caudally instead of rostrally as they are in all other mammals studied. The variant somatotopy appears to reflect the postural differences between flying and walking mammals, supporting the notion that topographical maps may have functional significance apart from their point-to-point connections with the sensory periphery.