Synergistic Transcriptional Changes in AMPA and GABAA Receptor Genes Support Compensatory Plasticity Following Unilateral Hearing Loss.

Debilitating perceptual disorders including tinnitus, hyperacusis, phantom limb pain and visual release hallucinations may reflect aberrant patterns of neural activity in central sensory pathways following a loss of peripheral sensory input. Here, we explore short- and long-term changes in gene expression that may contribute to hyperexcitability following a sudden, profound loss of auditory input from one ear. We used fluorescence in situ hybridization to quantify mRNA levels for genes encoding AMPA and GABAA receptor subunits (Gria2 and Gabra1, respectively) in single neurons from the inferior colliculus (IC) and auditory cortex (ACtx). Thirty days after unilateral hearing loss, Gria2 levels were significantly increased while Gabra1 levels were significantly decreased. Transcriptional rebalancing was more pronounced in ACtx than IC and bore no obvious relationship to the degree of hearing loss. By contrast to the opposing, synergistic shifts in Gria2 and Gabra1 observed 30 days after hearing loss, we found that transcription levels for both genes were equivalently reduced after 5 days of hearing loss, producing no net change in the excitatory/inhibitory transcriptional balance. Opposing transcriptional shifts in AMPA and GABA receptor genes that emerge several weeks after a peripheral insult could promote both sensitization and disinhibition to support a homeostatic recovery of neural activity following auditory deprivation. Imprecise transcriptional changes could also drive the system toward perceptual hypersensitivity, degraded temporal processing and the irrepressible perception of non-existent environmental stimuli, a trio of perceptual impairments that often accompany chronic sensory deprivation.

Crystal, magnetic, calorimetric and electronic structure investigation of GdScGe1-x Sb x compounds.

Experimental investigations of crystal structure, magnetism and heat capacity of compounds in the pseudoternary GdScGe-GdScSb system combined with density functional theory projections have been employed to clarify the interplay between the crystal structure and magnetism in this series of RTX materials (R = rare-earth, [Formula: see text] = transition metal and X = p-block element). We demonstrate that the CeScSi-type structure adopted by GdScGe and CeFeSi-type structure adopted by GdScSb coexist over a limited range of compositions [Formula: see text]. Antimony for Ge substitutions in GdScGe result in an anisotropic expansion of the unit cell of the parent that is most pronounced along the c axis. We believe that such expansion acts as the driving force for the instability of the double layer CeScSi-type structure of the parent germanide. Extensive, yet limited Sb substitutions [Formula: see text] lead to a strong reduction of the Curie temperature compared to the GdScGe parent, but without affecting the saturation magnetization. With a further increase in Sb content, the first compositions showing the presence of the CeFeSi-type structure of the antimonide, [Formula: see text], coincide with the appearance of an antiferromagnetic phase. The application of a finite magnetic field reveals a jump in magnetization toward a fully saturated ferromagnetic state. This antiferro-ferromagnetic transformation is not associated with a sizeable latent heat, as confirmed by heat capacity measurements. The electronic structure calculations for [Formula: see text] indicate that the key factor in the conversion from the ferromagnetic CeScSi-type to the antiferromagnetic CeFeSi-type structure is the disappearance of the induced magnetic moments on Sc. For the parent antimonide, heat capacity measurements indicate an additional transition below the main antiferromagnetic transition.

Noise-induced cochlear synaptopathy in rhesus monkeys (Macaca mulatta).

Cochlear synaptopathy can result from various insults, including acoustic trauma, aging, ototoxicity, or chronic conductive hearing loss. For example, moderate noise exposure in mice can destroy up to ∼50% of synapses between auditory nerve fibers (ANFs) and inner hair cells (IHCs) without affecting outer hair cells (OHCs) or thresholds, because the synaptopathy occurs first in high-threshold ANFs. However, the fiber loss likely impairs temporal processing and hearing-in-noise, a classic complaint of those with sensorineural hearing loss. Non-human primates appear to be less vulnerable to noise-induced hair-cell loss than rodents, but their susceptibility to synaptopathy has not been studied. Because establishing a non-human primate model may be important in the development of diagnostics and therapeutics, we examined cochlear innervation and the damaging effects of acoustic overexposure in young adult rhesus macaques. Anesthetized animals were exposed bilaterally to narrow-band noise centered at 2 kHz at various sound-pressure levels for 4 h. Cochlear function was assayed for up to 8 weeks following exposure via auditory brainstem responses (ABRs) and otoacoustic emissions (OAEs). A moderate loss of synaptic connections (mean of 12-27% in the basal half of the cochlea) followed temporary threshold shifts (TTS), despite minimal hair-cell loss. A dramatic loss of synapses (mean of 50-75% in the basal half of the cochlea) was seen on IHCs surviving noise exposures that produced permanent threshold shifts (PTS) and widespread hair-cell loss. Higher noise levels were required to produce PTS in macaques compared to rodents, suggesting that primates are less vulnerable to hair-cell loss. However, the phenomenon of noise-induced cochlear synaptopathy in primates is similar to that seen in rodents.

Glucagon-like peptide 1 receptor activation regulates cocaine actions and dopamine homeostasis in the lateral septum by decreasing arachidonic acid levels.

Agonism of the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) has been effective at treating aspects of addictive behavior for a number of abused substances, including cocaine. However, the molecular mechanisms and brain circuits underlying the therapeutic effects of GLP-1R signaling on cocaine actions remain elusive. Recent evidence has revealed that endogenous signaling at the GLP-1R within the forebrain lateral septum (LS) acts to reduce cocaine-induced locomotion and cocaine conditioned place preference, both considered dopamine (DA)-associated behaviors. DA terminals project from the ventral tegmental area to the LS and express the DA transporter (DAT). Cocaine acts by altering DA bioavailability by targeting the DAT. Therefore, GLP-1R signaling might exert effects on DAT to account for its regulation of cocaine-induced behaviors. We show that the GLP-1R is highly expressed within the LS. GLP-1, in LS slices, significantly enhances DAT surface expression and DAT function. Exenatide (Ex-4), a long-lasting synthetic analog of GLP-1 abolished cocaine-induced elevation of DA. Interestingly, acute administration of Ex-4 reduces septal expression of the retrograde messenger 2-arachidonylglycerol (2-AG), as well as a product of its presynaptic degradation, arachidonic acid (AA). Notably, AA reduces septal DAT function pointing to AA as a novel regulator of central DA homeostasis. We further show that AA oxidation product γ-ketoaldehyde (γ-KA) forms adducts with the DAT and reduces DAT plasma membrane expression and function. These results support a mechanism in which postsynaptic septal GLP-1R activation regulates 2-AG levels to alter presynaptic DA homeostasis and cocaine actions through AA.

Cytological comparison of fine-needle aspirates of liver and spleen of normal dogs and of dogs with cutaneous mast cell tumours and an ultrasonographically normal appearing liver and spleen.

Staging of dogs with cutaneous mast cell tumours (MCTs) is an important diagnostic step. Aspiration of the liver and the spleen is often part of routine staging. This study cytologically compared mast cell numbers in fine-needle aspirates of liver and spleen of clinically normal unaffected dogs with those of dogs with cutaneous MCT and an ultrasonographically normal appearing liver and spleen. The unaffected dogs (n = 32) were selected from humane society dogs, and the affected dogs (n = 51) were selected from hospital cases. There were no statistically significant differences in each of the parameters evaluated for the liver aspirates. For splenic aspirates, affected dogs showed significantly more mast cells per cluster (P = 0.04) and more isolated mast cells per slide (P = 0.03) compared with unaffected dogs. However, no clinically important difference existed between the unaffected and affected dogs; thus, routine aspiration of an ultrasonographically normal appearing liver and spleen of dogs with cutaneous MCT does not appear to be a clinically useful staging tool.

Architectonic identification of the core region in auditory cortex of macaques, chimpanzees, and humans.

The goal of the present study was to determine whether the architectonic criteria used to identify the core region in macaque monkeys (Macaca mulatta, M. nemestrina) could be used to identify a homologous region in chimpanzees (Pan troglodytes) and humans (Homo sapiens). Current models of auditory cortical organization in primates describe a centrally located core region containing two or three subdivisions including the primary auditory area (AI), a surrounding belt of cortex with perhaps seven divisions, and a lateral parabelt region comprised of at least two fields. In monkeys the core region can be identified on the basis of specific anatomical and physiological features. In this study, the core was identified from serial sets of adjacent sections processed for cytoarchitecture, myeloarchitecture, acetylcholinesterase, and cytochrome oxidase. Qualitative and quantitative criteria were used to identify the borders of the core region in individual sections. Serial reconstructions of each brain were made showing the location of the core with respect to gross anatomical landmarks. The position of the core with respect to major sulci and gyri in the superior temporal region varied most in the chimpanzee and human specimens. Although the architectonic appearance of the core areas did vary in certain respects across taxonomic groups, the numerous similarities made it possible to identify unambiguously a homologous cortical region in macaques, chimpanzees, and humans.

Sensory enrichment after peripheral nerve injury restores cortical, not thalamic, receptive field organization.

Sensory perception can be severely degraded after peripheral injuries that disrupt the functional organization of the sensory maps in somatosensory cortex, even after nerve regeneration has occurred. Rehabilitation involving sensory retraining can improve perceptual function, presumably through plasticity mechanisms in the somatosensory processing network. However, virtually nothing is known about the effects of rehabilitation strategies on brain organization, or where the effects are mediated. In this study, five macaque monkeys received months of enriched sensory experience after median nerve cut and repair early in life. Subsequently, the sensory representation of the hand in primary somatosensory cortex was mapped using multiunit microelectrodes. Additionally, the primary somatosensory relay in the thalamus, the ventroposterior nucleus, was studied to determine whether the effects of the enrichment were initiated subcortically or cortically. Age-matched controls included six monkeys with no sensory manipulation after median nerve cut and regeneration, and one monkey that had restricted sensory experience after the injury. The most substantial effect of the sensory environment was on receptive field sizes in cortical area 3b. Significantly greater proportions of cortical receptive fields in the enriched monkeys were small and well localized compared to the controls, which showed higher proportions of abnormally large or disorganized fields. The refinements in receptive field size and extent in somatosensory cortex likely provide better resolution in the sensory map and may explain the improved functional outcomes after rehabilitation in humans.

Subdivisions of auditory cortex and processing streams in primates.

The auditory system of monkeys includes a large number of interconnected subcortical nuclei and cortical areas. At subcortical levels, the structural components of the auditory system of monkeys resemble those of nonprimates, but the organization at cortical levels is different. In monkeys, the ventral nucleus of the medial geniculate complex projects in parallel to a core of three primary-like auditory areas, AI, R, and RT, constituting the first stage of cortical processing. These areas interconnect and project to the homotopic and other locations in the opposite cerebral hemisphere and to a surrounding array of eight proposed belt areas as a second stage of cortical processing. The belt areas in turn project in overlapping patterns to a lateral parabelt region with at least rostral and caudal subdivisions as a third stage of cortical processing. The divisions of the parabelt distribute to adjoining auditory and multimodal regions of the temporal lobe and to four functionally distinct regions of the frontal lobe. Histochemically, chimpanzees and humans have an auditory core that closely resembles that of monkeys. The challenge for future researchers is to understand how this complex system in monkeys analyzes and utilizes auditory information.

Thalamic and cortical contributions to neural plasticity after limb amputation.

Little is known about the substrates for the large-scale shifts in the cortical representation produced by limb amputation. Subcortical changes likely contribute to the cortical remodeling, yet there is little data regarding the extent and pattern of reorganization in thalamus after such a massive deafferentation. Moreover, the relationship between changes in thalamus and in cortex after injuries of this nature is virtually unexplored. Multiunit microelectrode maps were made in the somatosensory thalamus and cortex of two monkeys that had long-standing, accidental forelimb amputations. In the deprived portion of the ventroposterior nucleus of the thalamus (VP), where stimulation to the hand would normally activate neurons, new receptive fields had emerged. At some recording sites within the deprived zone of VP, neurons responded to stimulation of the remaining stump of the arm and at other sites neurons responded to stimulation of both the stump and the face. This same overall pattern of reorganization was present in the deprived hand representation of cortical area 3b. Thus thalamic changes produced by limb amputation appear to be an important substrate of cortical reorganization. However, a decrease in the frequency of abnormal stump/face fields in area 3b compared with VP and a reduction in the size of the fields suggests that cortical mechanisms of plasticity may refine the information relayed from thalamus.

'What' and 'where' processing in auditory cortex.

Tracing of auditory cortical connections suggests that the primate auditory system, like the visual and somatosensory systems, may be organized into 'what' and 'where' pathways.

Auditory processing in primate cerebral cortex.

Auditory information is relayed from the ventral nucleus of the medial geniculate complex to a core of three primary or primary-like areas of auditory cortex that are cochleotopically organized and highly responsive to pure tones. Auditory information is then distributed from the core areas to a surrounding belt of about seven areas that are less precisely cochleotopic and generally more responsive to complex stimuli than tones. Recent studies indicate that the belt areas relay to the rostral and caudal divisions of a parabelt region at a third level of processing in the cortex lateral to the belt. The parabelt and belt regions have additional inputs from dorsal and magnocellular divisions of the medial geniculate complex and other parts of the thalamus. The belt and parabelt regions appear to be concerned with integrative and associative functions involved in pattern perception and object recognition. The parabelt fields connect with regions of temporal, parietal, and frontal cortex that mediate additional auditory functions, including space perception and auditory memory.

Callosal connections of the parabelt auditory cortex in macaque monkeys.

Auditory cortex of macaque monkeys is located on the lower bank of the lateral sulcus and the adjoining superior temporal gyrus. This region of cortex contains a core of primary-like areas surrounded by a narrow belt of associated fields. Adjacent to the lateral belt on the superior temporal gyrus is a parabelt region which contains at least two subdivisions (rostral and caudal). In previous studies we defined the parabelt region as cortex with topographic cortical connections with the belt areas surrounding the core, and connections with the dorsal and magnocellular divisions of the medial geniculate complex, but minimal connections with the core region and ventral division of the medial geniculate complex. The callosal connections of the parabelt auditory cortex were determined by placing injections, of up to six distinguishable tracers, into different locations of the parabelt region in each of four macaque monkeys. The results indicated that the strongest callosal projections arise from homotopic areas in parabelt cortex, and they roughly matched the rostrocaudal levels of the medial and lateral belt cortex. Weaker callosal inputs to the parabelt originate from the corresponding levels of the superior temporal gyrus and superior temporal sulcus. The core region does not contribute significant callosal projections to the parabelt region. The results provide further support for the conclusion that the parabelt region represents a third level of auditory cortical processing beyond direct activation by primary subcortical and cortical auditory structures.

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.

Thalamocortical connections of the parabelt auditory cortex in macaque monkeys.

The auditory cortex of macaque monkeys contains a core of primary-like areas surrounded by a narrow belt of associated fields that encompass much of the superior temporal plane in these animals. Adjacent to the lateral belt on the superior temporal gyrus is a parabelt region that contains at least two subdivisions (rostral and caudal). In a previous study (Hackett et al. [1998] J. Comp. Neurol. 394:475-495), we determined that the parabelt has topographic connections with the belt areas surrounding the core, but minimal connections with the core itself. In this study, we describe the thalamocortical connections of the parabelt auditory cortex based on multiple injections of neuronal tracers into this region in each of five macaque monkeys. Injections confined to the parabelt labeled large numbers of neurons in the dorsal (MGd) and magnocellular (MGm) divisions of the medial geniculate complex (MGC), suprageniculate (Sg), limitans (Lim), and medial pulvinar (PM) nuclei. Only when injections encroached on the lateral belt cortex were substantial numbers of labeled neurons found in the ventral (MGv) division of the MGC, consistent with the absence of significant connections between the parabelt and core fields. The rostrocaudal topography of the parabelt region was maintained in the thalamocortical connections, supporting the parcellation of this region of cortex. The results suggest that the parabelt region represents a third level of auditory cortical processing, which is not influenced by direct inputs from primary cortical or subcortical auditory structures.

Subdivisions of auditory cortex and ipsilateral cortical connections of the parabelt auditory cortex in macaque monkeys.

Auditory cortex of macaque monkeys can be divided into a core of primary or primary-like areas located on the lower bank of the lateral sulcus, a surrounding narrow belt of associated fields, and a parabelt region just lateral to the belt on the superior temporal gyrus. We determined patterns of ipsilateral cortical connections of the parabelt region by placing injections of four to seven distinguishable tracers in each of five monkeys. Results were related to architectonic subdivisions of auditory cortex in brain sections cut parallel to the surface of artificially flattened cortex (four cases) or cut in the coronal plane (one case). An auditory core was clearly apparent in these sections as a 16- to 20-mm rostrocaudally elongated oval, several millimeters from the lip of the sulcus, that stained darkly for parvalbumin, myelin, and acetylcholinesterase. These features were most pronounced caudally in the cortex assigned to auditory area I, only slightly reduced in the rostral area, and most reduced in the narrower rostral extension we define as the rostrotemporal area. A narrow band of cortex surrounding the core stained more moderately for parvalbumin, acetylcholinesterase, and myelin. Two regions of the caudal belt, the caudomedial area, and the mediolateral area, stained more darkly, especially for parvalbumin. Rostromedial and medial rostrotemporal, regions of the medial belt stained more lightly for parvalbumin than the caudomedial area or the lateral belt. The parabelt region stained less darkly than the core and belt fields. Injections confined to the parabelt region labeled few neurons in the core, but large numbers in parts of the belt, the parabelt, and adjacent portions of the temporal lobe. Injections that encroached on the belt labeled large numbers of neurons in the core and helped define the width of the belt. Caudal injections in the parabelt labeled caudal portions of the belt, rostral injections labeled rostral portions, and both caudal and rostral injections labeled neurons in the rostromedial area of the medial belt. These observations support the concept of dividing the auditory cortex into core, belt, and parabelt; provide evidence for including the rostral area in the core; suggest the existence of as many as seven or eight belt fields; provide evidence for at least two subdivisions of the parabelt; and identify regions of the temporal lobe involved in auditory processing.

Subdivisions of auditory cortex and levels of processing in primates.

In a series of experiments on New World and Old World monkeys, architectonic features of auditory cortex were related to tone frequency maps and patterns of connections to generate and evaluate theories of cortical organization. The results suggest that cortical processing of auditory information involves a number of functionally distinct fields that can be broadly grouped into four or more levels of processing. At the first level, there are three primary-like areas, each with a discrete pattern of tonotopic organization, koniocortical histological features, and direct inputs from the ventral division of the medial geniculate complex. These three core areas are interconnected and project to a narrow surrounding belt of perhaps seven areas which receive thalamic input from the major divisions of the medial geniculate complex, the suprageniculate/limitans complex, and the medial pulvinar. The belt areas connect with a lateral parabelt region of two or more fields that are almost devoid of direct connections with the core and the ventral division of the medial geniculate complex. The parabelt fields connect with more distant cortex in the superior temporal gyrus, superior temporal sulcus, and prefrontal cortex. The results indicate that auditory processing involves 15 or more cortical areas, each of which is interconnected with a number of other fields, especially adjoining fields of the same level.