Haloperidol-induced catalepsy is ameliorated by deep brain stimulation of the inferior colliculus.

Deep brain stimulation (DBS) has evolved as a promising alternative treatment for Parkinson's disease (PD), but the underlying mechanisms remain poorly understood. Moreover, conventional DBS protocols targeted at basal ganglia sites can turn out completely ineffective for some PD patients, warranting the search for alternative targets. The inferior colliculus (IC) is a midbrain auditory relay station involved in sensorimotor processes. High-frequency 2500 Hz electrical stimulation of the IC elicits escape behaviour and interferes with haloperidol-induced catalepsy in rats, a state reminiscent of Parkinsonian akinesia, but clinical implication is limited since the protocol is aversive. However, typical DBS stimulation frequencies range between 20-180 Hz. We therefore tested the effects of a low-frequency 30 Hz-DBS protocol on haloperidol-induced catalepsy and aversive behaviour in rats. We show that low-frequency 30 Hz-DBS targeted at the IC strongly ameliorates haloperidol-induced catalepsy without any evidence of stimulation-induced escape behaviour. Furthermore, 30 Hz-DBS of the IC produced no place avoidance in a place conditioning paradigm and induced no anxiety-related behaviour on the elevated plus maze, indicating that the protocol has no aversive or anxiogenic side effects. Our findings provide first evidence that the IC can serve as an alternative, non-conventional DBS target.

Inferior colliculus stimulation causes similar efferent effects on ipsilateral and contralateral cochlear potentials in the guinea pig.

The inferior colliculus (IC) is a processing center in both the ascending and descending auditory pathways. It has been demonstrated anatomically to send descending projections to the region of the medial olivocochlear (MOC) neurons in the auditory brainstem. Activation of MOC system produces reductions in cochlear neural activity. Individual MOC fibers innervate relatively restricted regions of the cochlea. Recent studies have shown that selective electrical stimulation within the IC central nucleus (ICC) produces frequency-specific reductions of neural activity in the contralateral cochlea (Ota, Y., Oliver, D.L., Dolan, D.F., 2004. Frequency-specific effects on cochlear responses during activation of the inferior colliculus in the guinea pig. J. Neurophysiol. 91, 2185-2193). This efferent effect is likely mediated through selective activation of MOC cells. In this study, we investigated the effects of selective stimulation of one ICC on cochlear output in both ears in anesthetized and paralyzed guinea pigs to explore possible differences in the effective efferent innervation of the two ears. ICC stimulation had a similar tonotopically tuned effect on the distortion product otoacoustic emission (DPOAE) and the cochlear whole-nerve action potential (CAP) in each cochlea. The bandwidth of the efferent effect in each ear was measured and compared at different stimulation levels. For a given ICC stimulation site, the efferent effects were larger for the CAP response. The effect on each response measure was greater in the contralateral than the ipsilateral ear. The effective bandwidth of the efferent effect on the CAP was current-level-dependent but less so for the DPOAE. The results of transections at various locations within the brainstem suggest that the effects were mediated by the MOC system. From the results presented here, the descending efferent system, which originates in the auditory cortex, has frequency-specific, spatially restricted, bilateral effects. The effects are greater in the contralateral ear.

Interactions between opioid-peptides-containing pathways and GABA(A)-receptors-mediated systems modulate panic-like-induced behaviors elicited by electric and chemical stimulation of the inferior colliculus.

Aiming to clarify the effect of interactive interconnections between the endogenous opioid peptides-neural links and GABAergic pathways on panic-like responses, in the present work, the effect of the peripheral and central administration of morphine or the non-specific opioid receptors antagonist naloxone was evaluated on the fear-induced responses (defensive attention, defensive immobility and escape behavior) elicited by electric and chemical stimulation of the inferior colliculus. Central microinjections of opioid drugs in the inferior colliculus were also performed followed by local administration of the GABA(A)-receptor antagonist bicuculline. The defensive behavior elicited by the blockade of GABAergic receptors in the inferior colliculus had been quantitatively analyzed, recording the number of crossing, jump, rotation and rearing, in each minute, during 30 min, in the open-field test. The opioid receptors stimulation with morphine decreased the defensive attention, the defensive immobility and escape behavior thresholds, and the non-specific opioid receptors blockade caused opposite effects, enhancing the defensive behavior thresholds. These effects were corroborated by either the stimulation or the inhibition of opioid receptors followed by the GABA(A) receptor blockade with bicuculline, microinjected into the inferior colliculus. There was a significant increase in the diverse fear-induced responses caused by bicuculline with the pretreatment of the inferior colliculus with morphine, and the opposite effect was recorded after the pretreatment of the inferior colliculus nuclei with naloxone followed by bicuculline local administration. These findings suggest an interaction between endogenous opioid-peptides-containing connections and GABA(A)-receptor-mediated system with direct influence on the organization of the panic-like or fear-induced responses elaborated in the inferior colliculus during critical emotional states.

Unilateral electrical stimulation of the inferior colliculus of rats modifies the prepulse modulation of the startle response (PPI): effects of ketamine and diazepam.

The magnitude of an acoustic startle response can be reduced by a weak stimulus presented immediately before the startle-eliciting noise. This phenomenon has been termed prepulse inhibition of the startle reaction (PPI). Previous studies indicated that the primary neural pathways mediating PPI belong to the brain stem and that the inferior colliculus (IC) was crucial. Its destruction reduced PPI. Stimulations applied to brain areas may be as deleterious as lesions. Therefore, we looked for the possibility of a brain stimulation applied to the IC during a PPI test to reduce also PPI. Rats were implanted with chronic electrodes, their tips being aimed at the IC. They were located within or close to the inter-colliculus nucleus. A train of stimulations was applied and PPI was tested alternately during and between periods of stimulation. As the most common method used to attenuate PPI consists in administrating drugs, for example ketamine, we also tested the effect of this drug. Another drug was also tested, diazepam, since it alters the functioning of the IC without any known effect on PPI. This allowed a comparative analysis of the neurobiological and the pharmacological effects. It appeared that the stimulation decreased PPI quantitatively as much as ketamine (6 mg/kg) without an effect of the basic startle reaction. These effects did not interfere with each other. Diazepam (1 mg/kg) did not modify PPI, neither under stimulation nor per se. Only for a very high dose (4 mg/kg), a sedative and myo-relaxant one the basic startle and PPI were altered.

Radiant energy required for infrared neural stimulation.

Infrared neural stimulation (INS) has been proposed as an alternative method to electrical stimulation because of its spatial selective stimulation. Independent of the mechanism for INS, to translate the method into a device it is important to determine the energy for stimulation required at the target structure. Custom-designed, flat and angle polished fibers, were used to deliver the photons. By rotating the angle polished fibers, the orientation of the radiation beam in the cochlea could be changed. INS-evoked compound action potentials and single unit responses in the central nucleus of the inferior colliculus (ICC) were recorded. X-ray computed tomography was used to determine the orientation of the optical fiber. Maximum responses were observed when the radiation beam was directed towards the spiral ganglion neurons (SGNs), whereas little responses were seen when the beam was directed towards the basilar membrane. The radiant exposure required at the SGNs to evoke compound action potentials (CAPs) or ICC responses was on average 18.9 ± 12.2 or 10.3 ± 4.9 mJ/cm(2), respectively. For cochlear INS it has been debated whether the radiation directly stimulates the SGNs or evokes a photoacoustic effect. The results support the view that a direct interaction between neurons and radiation dominates the response to INS.

The role of phase changes in sound signals in localization of sound sources.

The auditory system in humans and animals makes virtually no discrimination of phase changes in the structure of monaurally presented sound signals. However, electrophysiological studies have demonstrated marked changes in the responses of the central parts of the auditory system when the phase structure of the signal changes during presentation of the same type of stimulation. We have suggested that this inconsistency is due to the preparative role of phase effects during monaural stimulation for subsequent operations in the auditory system involved in determining the location of a sound source in space. This report presents experimental data on defined changes (increases in amplitude) in the electrical responses of the midbrain center of the auditory system (inferior colliculus) in antiphase binaural presentation of series of sound impulses (comparison with synphase presentation). These changes may be part of the mechanism underlying the interference resistance of the auditory system during determination of the location of a sound source (binaural release from masking). Neuronal cortical activity is sensitive and selective to dynamic interaural changes in the phase spectrum of the signal, which may provide the basis of the mechanism for locating a moving sound source. Auditory evoked potentials in humans demonstrate memorizing of the direction of movement of a sound image, as shown by the changes in parameters on presentation of stimuli of different locations (deviant stimuli) differing from the standard parameters of mismatch negativity.

Infrared neural stimulation: beam path in the guinea pig cochlea.

It has been demonstrated that INS can be utilized to stimulate spiral ganglion cells in the cochlea. Although neural stimulation can be achieved without direct contact of the radiation source and the tissue, the presence of fluids or bone between the target structure and the radiation source may lead to absorption or scattering of the radiation, which may limit the efficacy of INS. The present study demonstrates the neural structures in the radiation beam path that can be stimulated. Histological reconstructions and microCT of guinea pig cochleae stimulated with an infrared laser suggest that the orientation of the beam from the optical fiber determined the site of stimulation in the cochlea. Best frequencies of the INS-evoked neural responses obtained from the central nucleus of the inferior colliculus matched the histological sites in the spiral ganglion.

Spatial selectivity to intracochlear electrical stimulation in the inferior colliculus is degraded after long-term deafness in cats.

In an animal model of electrical hearing in prelingually deaf adults, this study examined the effects of deafness duration on response thresholds and spatial selectivity (i.e., cochleotopic organization, spatial tuning and dynamic range) in the central auditory system to intracochlear electrical stimulation. Electrically evoked auditory brain stem response (EABR) thresholds and neural response thresholds in the external (ICX) and central (ICC) nuclei of the inferior colliculus were estimated in cats after varying durations of neonatally induced deafness: in animals deafened <1.5 yr (short-deafened unstimulated, SDU cats) with a mean spiral ganglion cell (SGC) density of approximately 45% of normal and in animals deafened >2.5 yr (long-deafened, LD cats) with severe cochlear pathology (mean SGC density <7% of normal). LD animals were subdivided into unstimulated cats and those that received chronic intracochlear electrical stimulation via a feline cochlear implant. Acutely deafened, implanted adult cats served as controls. Independent of their stimulation history, LD animals had significantly higher EABR and ICC thresholds than SDU and control animals. Moreover, the spread of electrical excitation was significantly broader and the dynamic range significantly reduced in LD animals. Despite the prolonged durations of deafness the fundamental cochleotopic organization was maintained in both the ICX and the ICC of LD animals. There was no difference between SDU and control cats in any of the response properties tested. These findings suggest that long-term auditory deprivation results in a significant and possibly irreversible degradation of response thresholds and spatial selectivity to intracochlear electrical stimulation in the auditory midbrain.

Increases in extracellular levels of 5-HT and dopamine in the basolateral, but not in the central, nucleus of amygdala induced by aversive stimulation of the inferior colliculus.

Consistent evidence has shown that dopamine release in the prefrontal cortex is increased by electrical stimulation of the inferior colliculus (IC) as unconditioned stimulus. Recent reports have also demonstrated that inactivation of the basolateral nucleus of the amygdala (BLA) with muscimol enhances the behavioural consequences of the aversive stimulation of the IC and reduces the dopamine release in the prefrontal cortex. Moreover, neurotoxic lesions of the BLA enhance whereas those of the central nucleus of the amygdala (CeA) reduce the aversiveness of the electrical stimulation of the IC. Based on these findings the present study examined the effects of the electrical stimulation of the IC on the extracellular levels of serotonin and dopamine in the BLA and CeA. To this end, rats implanted with a stimulation electrode in the IC also bore a microdialysis probe in the BLA or CeA for determination of the release of dopamine and serotonin. IC electrical stimulation at the freezing and escape thresholds increased the levels of serotonin ( approximately 70%) and dopamine ( approximately 60%) in the BLA related to the basal values. Similarly, the metabolites DOPAC and 5-HIAA increased in a parallel fashion in BLA. No significant changes could be detected in these biogenic amines and metabolites in CeA following IC aversive stimulation. These findings point to a differential role of serotonergic and dopaminergic mechanisms of the BLA and CeA in the setting up of adaptive responses to fear states generated at the inferior colliculus level.

Aversive stimulation of the inferior colliculus changes dopamine and serotonin extracellular levels in the frontal cortex: modulation by the basolateral nucleus of amygdala.

We have shown that stimulation of the neural substrates in the inferior colliculus (IC) causes a significant increase in the extracellular levels of dopamine (DA) in frontal cortex (FC). Also, it has been reported that the basolateral complex of the amygdala (BLA) serves as a filter for unconditioned and conditioned aversive information that ascend to higher structures from the brainstem. Linking these two kinds of information, this work examines whether inactivation of BLA interferes with the activation of cortical dopaminergic outputs produced by aversive stimulation of the IC. To this end, rats were implanted with an electrode in the IC for the determination of the threshold of escape responses. Each rat also bore a cannula implanted in the BLA for injections of lidocaine (10 microg/0.5 microL), muscimol (0.5 microg/0.5 microL), or its vehicle and a microdialysis probe in the FC for determination of the amount of DA and serotonin (5-HT). The data obtained show that IC electrical stimulation caused an increase in the DA release while it reduced the 5-HT release in the FC. BLA inactivation with both lidocaine or muscimol enhanced the aversiveness of the electrical stimulation of the IC and attenuated the increase in DA, while the reduction in 5-HT release in the FC remained unaffected. These findings suggest that ascending aversive information from IC on their way up to higher structures in the SNC courses with opposite modulation by DA/5-HT mechanisms in the FC. These processes are regulated by filters located in the BLA. It is proposed that the loss of these BLA regulatory mechanisms prevents the expression of these modulatory mechanisms in the FC that are adaptive responses in order to cope with unconditioned aversive stimulus triggered at the brainstem level.

Corticofugal feedback for auditory midbrain plasticity elicited by tones and electrical stimulation of basal forebrain in mice.

The auditory cortex (AC) is the major origin of descending auditory projections and is one of the targets of the cholinergic basal forebrain, nucleus basalis (NB). In the big brown bat, cortical activation evokes frequency-specific plasticity in the inferior colliculus and the NB augments this collicular plasticity. To examine whether cortical descending function and NB contributions to collicular plasticity are different between the bat and mouse and to extend the findings in the bat, we induced plasticity in the central nucleus of the mouse inferior colliculus by a tone paired with electrical stimulation of the NB (hereafter referred to as tone-ES(NB)). We show here that tone-ES(NB) shifted collicular best frequencies (BFs) towards the frequency of the tone paired with ES(NB) when collicular BFs were different from tone frequency. The shift in collicular BF was linearly correlated to the difference between collicular BFs and tone frequencies. The changes in collicular BFs after tone-ES(NB) were similar to those found in the big brown bat. Compared with cortical plasticity evoked by tone-ES(NB), the pattern of collicular BF shifts was identical but the shifting range of collicular BFs was narrower. A GABA(A) agonist (muscimol) or a muscarinic acetylcholine receptor antagonist (atropine) applied to the AC completely abolished the collicular plasticity evoked by tone-ES(NB). Therefore, our findings strongly suggest that the AC plays a critical role in experience-dependent auditory plasticity through descending projections.

Role of GABAergic inhibition in the coding of interaural time differences of low-frequency sounds in the inferior colliculus.

A major cue for the localization of sound in space is the interaural time difference (ITD). We examined the role of inhibition in the shaping of ITD responses in the inferior colliculus (IC) by iontophoretically ejecting gamma-aminobutyric acid (GABA) antagonists and GABA itself using a multibarrel pipette. The GABA antagonists block inhibition, whereas the applied GABA provides a constant level of inhibition. The effects on ITD responses were evaluated before, during and after the application of the drugs. If GABA-mediated inhibition is involved in shaping ITD tuning in IC neurons, then applying additional amounts of this inhibitory transmitter should alter ITD tuning. Indeed, for almost all neurons tested, applying GABA reduced the firing rate and consequently sharpened ITD tuning. Conversely, blocking GABA-mediated inhibition increased the activity of IC neurons, often reduced the signal-to-noise ratio and often broadened ITD tuning. Blocking GABA could also alter the shape of the ITD function and shift its peak suggesting that the role of inhibition is multifaceted. These effects indicate that GABAergic inhibition at the level of the IC is important for ITD coding.

Specializations for aerial hawking in the echolocation system of Molossus molossus (Molossidae, Chiroptera).

While searching for prey, Molossus molossus broadcasts narrow-band calls of 11.42 ms organized in pairs of pulses that alternate in frequency. The first signal of the pair is at 34.5 kHz, the second at 39.6 kHz. Pairs of calls with changing frequencies were only emitted when the interpulse intervals were below 200 ms. Maximum duty cycles during search phase are close to 20%. Frequency alternation of search calls is interpreted as a mechanism for increasing duty cycle and thus the temporal continuity of scanning, as well as increasing the detection range. A neurophysiological correlate for the processing of search calls was found in the inferior colliculus. 64% of neurons respond to frequencies in the 30- to 40-kHz range and only in this frequency range were closed tuning curves found for levels below 40 dB SPL. In addition, 15% of the neurons have double-tuned frequency-threshold curves with best thresholds at 34 and 39 kHz. Differing from observations in other bats, approach calls of M. molossus are longer and of higher frequencies than search calls. Close to the roost, the call frequency is increased to 45.0-49.8 kHz and, in addition, extremely broadband signals are emitted. This demonstrates high plasticity of call design.