Anatomical changes of the GABAergic system in the inferior colliculus of the genetically epilepsy-prone rat

The number of GABAergic neurons as determined by GAD immunocytochemistry and total neurons as determined from Nissl preparations were counted and classified at the light microscopic level in the inferior colliculus (IC) of the genetically epilepsy prone rat (GEPR) and the non-epileptic Sprague-Dawley (SD) strain of rat. GAD-positive neurons are abundant in the IC and a significant increase in the number of GAD-positive neurons occurs in the GEPR as compared to the SD in all three subdivisions. However, the most pronounced difference occurs in the ventral lateral portion of the central nucleus, where there is a selective increase in the small (200%) and medium-sized (90%) GABAergic somata (10-15 microns in diameter and 15-25 microns in diameter, respectively). As determined from Nissl preparations an increase in total numbers of neurons also occurs. Thus, a 100% increase in the number of small neurons and a 30% increase in the number of medium-sized neurons occur in the adult GEPR as compared to the SD rat. A statistically significant increase in the numbers of small neurons also occurred in the IC of the young GEPR. At 4 days of age, a 55% increase in the number of small neurons was found, and at 10 days of age this increase was 105%. The numbers of the medium and large neurons were similar in the older group of rats. These data suggest that the increase in cell number observed in the adult GEPR is not compensatory to the seizure activity, but may either be genetically programmed or be a failure of cell death. Based on other studies of genetic models of epilepsy, we propose that the additional GABAergic neurons may disinhibit excitatory projection neurons in the IC.     

Genetic Analysis of the Predisposition to Audiogenic Seizure Fits in Krushinsky-Molodkina Rat Strain

The expression of audiogenic seizure fits has been studied in F₁ hybrids between audiogenic seizure-prone Krushinsky-Molodkina rat strain and Wistar rats not prone to audiogenic seizures, as well as in two backcross generations. Only 10% of F₁ hybrids exhibit audiogenic seizure fits, whereas the frequency of this character in two generations of their backcrosses with Krushinsky-Molodkina rats is about 50%. A digenic model with incomplete penetrance has been put forward to explain the control of audiogenic seizure fits. This model fits the data obtained: the theoretically expected distributions of the character in offsprings of different crosses do not differ significantly from those observed in experiments. The model explains why the distribution of the character is the same in the first and second backcross offsprings.     

Effect of destruction of the inferior colliculus on function of the echolocation system in horseshoe bats

The effect of unilateral and bilateral destruction of the inferior colliculus on the sensitivity of the auditory system, on parameters of the sonor signals, and on Doppler shift compensation in echo signals was studied in experiments on horseshoe bats (Rhinolophus ferrum-equinum). The results show that complete bilateral destruction of the inferior colliculus in bats does not lead to total disturbance of function of the auditory system but it sharply reduces the sensitivity of that system, as shown by a decrease in the maximal obstacle detection range and inability to respond to an insect emitting a feeble sound. It can also be concluded that the inferior colliculus plays a direct part in maintenance of the emission frequency and that different parts of the inferior colliculus play different roles in this process. The Doppler shift compensation effect requires preservation of the integrity of not less than half of the central nucleus of at least one inferior colliculus.A. A. Ukhtomskii Physiological Institute, A. A. Zhdanov State University, Leningrad. Translated from Neirofiziologiya, Vol. 12, No. 4, pp. 375–381, July–August, 1980.     

Ascending and descending projections to the inferior colliculus in the rat

The ascending and descending projections to the central nucleus of the inferior colliculus (IC) were studied with the aid of retrograde transport of horseradish peroxidase (HRP). HRP-labelled cells were found in contralateral cochlear nuclei, where the majority of different cell types was stained. Few labelled cells were observed in the ipsilateral cochlear nuclei. HRP-positive neurones were found in all nuclei of the superior olivary complex on the ipsilateral side with the exception of the medial nucleus of the trapezoid body, which was never labelled either ipsilaterally or contralaterally. The largest concentration of HRP-labelled cells was usually observed in the ipsilateral superior olivary nucleus. Smaller numbers of labelled cells were present in contralateral nuclei of the superior olivary complex. Massive projections to the inferior colliculus were found from the contralateral and ipsilateral dorsal nucleus of the lateral lemniscus and ipsilateral ventral nucleus of the lateral lemniscus. Many neurones of the central and external nuclei of the contralateral inferior colliculus were labelled with HRP. Topographic organisation of the pathways ascending to the colliculus was expressed in the cochlear nuclei, lateral superior olivary nucleus and in the dorsal nucleus of the lateral lemniscus. HRP--positive cells were found in layer V of the ipsilateral auditory cortex, however, the evidence for topographic organisation was lacking.     

Corticofugal regulation of auditory sensitivity in the bat inferior colliculus

Under free-field stimulation conditions, corticofugal regulation of auditory sensitivity of neurons in the central nucleus of the inferior colliculus of the big brown bat, Eptesicus fuscus, was studied by blocking activities of auditory cortical neurons with Lidocaine or by electrical stimulation in auditory cortical neuron recording sites. The corticocollicular pathway regulated the number of impulses, the auditory spatial response areas and the frequency-tuning curves of inferior colliculus neurons through facilitation or inhibition. Corticofugal regulation was most effective at low sound intensity and was dependent upon the time interval between acoustic and electrical stimuli. At optimal interstimulus intervals, inferior colliculus neurons had the smallest number of impulses and the longest response latency during corticofugal inhibition. The opposite effects were observed during corticofugal facilitation. Corticofugal inhibitory latency was longer than corticofugal facilitatory latency. Iontophoretic application of γ-aminobutyric acid and bicuculline to inferior colliculus recording sites produced effects similar to what were observed during corticofugal inhibition and facilitation. We suggest that corticofugal regulation of central auditory sensitivity can provide an animal with a mechanism to regulate acoustic signal processing in the ascending auditory pathway. Accepted: 15 July 1998     

Neural modulation in inferior colliculus and central auditory plasticity

The neural modulation in central auditory system plays an important role in perception and processing of sound signal and auditory cognition. The inferior colliculus (IC) is both a relay station in central auditory pathway and a sub-cortical auditory center doing the sound signal processing. IC is also modulated by the descending projections from the cortex and auditory thalamus, medial geniculate body, and these neural modulations not only can affect ongoing sound signal processing but can also induce plastic changes in IC.     

Early morphological and functional changes in the GABAergic system of hippocampus in the rat lithium-pilocarpine model of epilepsy

We studied early alterations in the GABAergic system of the rat hippocampus in the lithium–pilocarpine model of epilepsy. Twenty-four hours after the pilocarpine treatment, a decrease in the number of calretinin-positive interneurons was observed in the CA1 field of the hippocampus, whereas the number of parvalbumin-positive interneurons remained unchanged. The decreased levels of the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD67) and the membrane GABA transporter GAT1 were revealed using Western blot analysis. These data indicate an altered excitation/inhibition balance in the hippocampus with excitation dominance.     

Reduced erythrocyte deformability in Krushinsky-Molodkina rats with acute hemorrhagic stroke

Acute hemorrhagic stroke in Krushinsky-Molodkina rats was used to assess the ability of erythrocytes to change their shape in a shear flow. Membrane rigidity and internal viscosity of erythrocytes were measured by laser diffractometry (i.e., obtaining a diffraction pattern from a thin layer of an erythrocyte suspension in a shear flow followed by computer processing of the image). The results testify to reduced deformability of erythrocytes under hemorrhagic stroke.     

Serotonin modulates responses to species-specific vocalizations in the inferior colliculus

Neuromodulators such as serotonin are capable of altering the neural processing of stimuli across many sensory modalities. In the inferior colliculus, a major midbrain auditory gateway, serotonin alters the way that individual neurons respond to simple tone bursts and linear frequency modulated sweeps. The effects of serotonin are complex, and vary among neurons. How serotonin transforms the responses to spectrotemporally complex sounds of the type normally heard in natural settings has been poorly examined. To explore this issue further, the effects of iontophoretically applied serotonin on the responses of individual inferior colliculus neurons to a variety of recorded species-specific vocalizations were examined. These experiments were performed in the Mexican free-tailed bat, a species that uses a rich repertoire of vocalizations for the purposes of communication as well as echolocation. Serotonin frequently changed the number of recorded calls that were capable of evoking a response from individual neurons, sometimes increasing (15% of serotonin-responsive neurons), but usually decreasing (62% of serotonin-responsive neurons), this number. A functional consequence of these serotonin-evoked changes would be to change the population response to species-specific vocalizations.     

Characteristics of borderline modulation frequencies in the differentiation of tonal and amplitude-modulated stimuli following the removal of the inferior colliculus in rats

Elaboration of differentiation between sound stimuli was carried out in 15 laboratory rats. After bilateral ablations of auditory inferior colliculi the border frequency of stimulus amplitude modulation was determined for all rats when they still could differentiate between tonal and amplitude-modulated stimuli. Decrease in frequency of modulation by 2 Hz and more from the border frequency caused a complete loss of ability to differentiate. In all rats bilateral inferior colliculi ablations completely disturbed differentiation between tonal and amplitude-modulated signals with modulation frequency below 183-191 Hz (the range of border frequencies). The surgery however did not affect differentiation between tonal and amplitude-modulated signals with the modulation frequencies above 183-191 Hz. The data suggest that the functions of completion of coding of amplitude-modulated stimuli in the auditory system is strictly linked with definite structures.     

Rats of Krushinsky-Molodkina strain: studies of audiogenic epilepsy, vascular pathology, and behavior

Physiological, biochemical and genetic studies of audiogenic epilepsy in Krushinsky-Molodkina (KM) rat strain are analyzed. In brief, the history of KM strain selection and its current state are reviewed. Physiological mechanisms of the typical audiogenic seizure development and the audiogenic myoclonus (audiogenic kindling phenomena) are considered. The EEG correlates of these phenomena are presented. Biochemical features of the strain (neurotransmitter and neuronal membrane biochemistry) are described.     

Functional changes in the septal GABAergic system of animals with a model of temporal lobe epilepsy

The septal GABAergic system plays a central role in the regulation of activity and excitability of the hippocampus (the main locus of temporal lobe epilepsy, TLE), but the character of changes the septum undergoes in this pathology remains unknown. To address this issue we studied the influences on GABAergic receptors in septal slices from the brain of epileptic guinea pigs compared to a control. In the epileptic brain, the overall increase in the mean frequency of neuronal discharges and the rise in the number of bursting neurons were revealed. The inhibitory action of exogenously applied GABA on neuronal activity is sharply enhanced, whereas the efficacy of action of GABA(A) and GABA(B) receptor blockers decreases, indicating the alteration of intraseptal inhibitory processes in epilepsy. In epilepsy, GABA sharply increases the oscillatory activity of the part of pacemakers, and the opposite effect was observed in the control. In epileptic animals, the GABA receptor blockers did not affect burst neurons, indicating the disturbance of the tonic GABAergic control of the oscillatory activity. Thus, we demonstrated for the first time that the activity of septal neurons and their reactions to GABAergic substances in animals with TLE model changed sharply compared to healthy ones.     

Postnatal development of vascularity in the inferior colliculus of the young rat

The inferior colliculus in the rat midbrain is an auditory relay center whose functional maturation occurs postnatally. We examined by morphometry the vascularity and the nuclear profile density of the inferior colliculus in normal young rats at different ages (before and after the onset of auditory input). We also compared this region with a frontal region of the cerebral cortex in 24-day-old rats. The inferior colliculus from aldehyde-perfused Sprague-Dawley rats aged 5, 9, 14, and 24 days was analyzed by light microscopy of semithin plastic sections. The central region (mostly the central nucleus) was sampled at 5 levels representing its entire rostrocaudal extent. Patent-blood-vessel profiles were counted and classified according to their size and profile orientation. Counts of nuclear profiles in the same sections were also made. In the inferior colliculus of rats between 5 and 24 days of age, the small (less than 10-microns diameter) cross-sectioned vessel profiles increased over 6-fold in number per unit area. Correspondingly the vascular volume density, estimated by differential point counting, increased between these ages. However, there was a decrease in the number of neuronal and glial nuclear profiles per unit area, probably because of growth in the volume of the neuronal perikarya and processes, along with cell emigration reported to occur at early postnatal ages. This study has shown that an increase in vascularity in the central region of the rat inferior colliculus continues for up to 2 weeks after the onset of hearing.(ABSTRACT TRUNCATED AT 250 WORDS)     

Binaural masking and sensitivity to interaural delay in the inferior colliculus.

The binaural masking level difference (BMLD) is a psychophysical effect whereby signals masked by a noise at one ear become unmasked by sounds reaching the other. BMLD effects are largest at low frequencies where they depend on signal phase, suggesting that part of the physiological mechanism responsible for the BMLD resides in cells that are sensitive to interaural time disparities. We have investigated a physiological basis for unmasking in the responses of delay-sensitive cells in the central nucleus of the inferior colliculus in anaesthetized guinea pigs. The masking effects of a binaurally presented noise, as a function of the masker delay, were quantified by measuring the number of discharges synchronized to the signal, and by measuring the masked threshold. The noise level for masking was lowest at the best delay for the noise. The mean magnitude of the unmasking across our neural population was similar to the human psychophysical BMLD under the same signal and masker conditions.     

Eye position influences auditory responses in primate inferior colliculus

We examined the frame of reference of auditory responses in the inferior colliculus in monkeys fixating visual stimuli at different locations. Eye position modulated the level of auditory responses in 33% of the neurons we encountered, but it did not appear to shift their spatial tuning. The effect of eye position on auditory responses was substantial-comparable in magnitude to that of sound location. The eye position signal appeared to interact with the auditory responses in at least a partly multiplicative fashion. We conclude that the representation of sound location in primate IC is distributed and that the frame of reference is intermediate between head- and eye-centered coordinates. The information contained in these neurons appears to be sufficient for later neural stages to calculate the positions of sounds with respect to the eyes.     

The inferior colliculus of the mustached bat has the frequency-vs-latency coordinates

In the mustached bat, the central auditory system contains FM–FM (delay-tuned) neurons which are specialized for processing target-distance information carried by echo delays. Mechanisms for creating the FM–FM neurons involve delay lines, coincidence detection and amplification. A neural basis for delay lines can be a map representing response latencies. The aim of the present study is to explore whether the central nucleus of the inferior colliculus has a latency axis incorporated into iso-best frequency slabs. Responses of single or multiple neurons were recorded from the inferior colliculus of unanesthetized mustached bats with tungsten-wire electrodes, and their response latencies were measured with tone bursts at their best frequencies and best amplitudes or 65 dB SPL. In the dorsoventral electrode penetrations across the inferior colliculus, response latency systematically shortens from ˜12 to ˜4␣ms. Tonotopic representation in the inferior colliculus is somewhat complex. Iso-best frequency slabs are tilted and/or curved, but they orient more or less ventrodorsally. Nevertheless, the latency axis is evident in each iso-best frequency slab, regardless of best frequency. The inferior colliculus has the frequency-vs-latency coordinates. Accepted: 2 October 1996     

Elevated levels of group-III metabotropic glutamate receptors in the inferior colliculus of genetically epilepsy-prone rats following intracollicular administration of l-serine-O-phosphate

The selective group-III metabotropic glutamate receptor agonist, L-serine-O-phosphate (L-SOP), when injected bilaterally into the inferior colliculus of the sound sensitive genetically epilepsy-prone (GEP) rats produces a short proconvulsant excitation followed by a long phase of protection against sound-induced seizures lasting for 2-4 days. We have studied this prolonged suppression of audiogenic seizures using pharmacological and molecular biological approaches including semiquantitative RT-PCR and western blotting. The intracerebroventricular injection of the protein synthesis inhibitor cycloheximide (120 microg) 30 min beforehand significantly reduces the proconvulsant seizure activity and the prolonged anticonvulsant effect of intracollicular L-SOP (500 nmol/side). The sensitive semiquantitative RT-PCR revealed a significant up-regulation in mGlu(4) and mGlu(7) mRNA levels in the inferior colliculus at 2 days (maximum suppression of audiogenic seizures) after intracollicular L-SOP injection compared with the non-injected, 2-day post-vehicle treated and 7-day (return to expressing audiogenic seizures) post-drug or vehicle-treated groups. No significant changes were observed in mGlu(6) or mGlu(8) mRNA expression levels in drug-treated compared with control groups. Examination of mGlu(4a) and mGlu(7a) protein levels using western blotting showed a significant increase in mGlu(7a) but no significant change in mGlu(4a) protein levels 2 days after L-SOP treatment compared with the control groups (non-injected and 2-day vehicle-injected group). These results suggest that up-regulation of mGlu(7) receptors is involved in the prolonged anticonvulsant effect of L-SOP against sound-induced seizures in GEP rats. The potential use of mGlu(7) agonists as novel anti-epileptic agents merits investigation.