Contralateral suppression of otoacoustic emissions in pre-school children.

BACKGROUND: Contralateral suppression of otoacoustic emissions (OAEs) may serve as an index of the medial olivocochlear (MOC) reflex. To date, this index has been studied in various populations but never in pre-school children. The purpose of this study was to fill this gap and describe how the MOC reflex affects the properties of transiently evoked OAEs (TEOAEs) in this age group. In addition, the influence of the presence of spontaneous OAEs (SOAEs) in the studied ear on the suppression of TEOAEs was also investigated. METHODS: TEOAEs with and without contralateral acoustic stimulation (CAS) by white noise were measured in 126 normally hearing pre-school children aged 3-6 years. The values of response levels, suppression by CAS, and signal-to-noise ratios (SNRs) of TEOAEs were investigated for the whole signal (global) and for half-octave frequency bands from 1 to 4 kHz. Only ears with SNR >6 dB were used in the analyses. SOAEs were acquired using the so-called synchronized SOAEs (SSOAEs) technique. RESULTS: Ears with SSOAEs had higher response levels and SNRs than ears without SSOAEs, and suppression was lower (0.58 dB compared to 0.85 dB). Only 22% of all studied ears had an SNR >20 dB, a level recommended in some studies for measuring suppression. There were no significant effects of age or gender on TEOAE suppression. CONCLUSIONS: Suppression levels for pre-school children did not differ appreciably from those of adults measured under similar conditions in other studies. Taken together with no effect of age in the data studied here, it seems that there is no effect of age on TEOAE suppression. However, we did find that the presence of SSOAEs had an effect on TEOAE suppression, a finding which has not been reported in earlier studies on different populations. We suggest that the presence of SSOAEs might be a crucial factor related to MOC function.

Synaptic-like vesicles and candidate transduction channels in mechanosensory terminals.

This article summarises progress to date over an exciting and very enjoyable first 15 years of collaboration with Bob Banks. Our collaboration began when I contacted him with (to me) an unexpected observation that a dye used to mark recycling synaptic vesicle membrane at efferent terminals also labelled muscle spindle afferent terminals. This observation led to the re-discovery of a system of small clear vesicles present in all vertebrate primary mechanosensory nerve terminals. These synaptic-like vesicles (SLVs) have been, and continue to be, the major focus of our work. This article describes our characterisation of the properties and functional significance of these SLVs, combining our complementary skills: Bob's technical expertise and encyclopaedic knowledge of mechanosensation with my experience of synaptic vesicles and the development of the styryl pyridinium dyes, of which the most widely used is FM1-43. On the way we have found that SLVs seem to be part of a constitutive glutamate secretory system necessary to maintain the stretch-sensitivity of spindle endings. The glutamate activates a highly unusual glutamate receptor linked to phospholipase D activation, which we have termed the PLD-mGluR. It has a totally distinct pharmacology first described in the hippocampus nearly 20 years ago but, like the SLVs that were first described over 50 years ago, has since been little researched. Yet, our evidence and literature searches suggest this glutamate/SLV/PLD-mGluR system is a ubiquitous feature of mechanosensory endings and, at least for spindles, is essential for maintaining mechanosensory function. This article summarises how this system integrates with the classical model of mechanosensitive channels in spindles and other mechanosensory nerve terminals, including hair follicle afferents and baroreceptors controlling blood pressure. Finally, in this time when there is an imperative to show translational relevance, I describe how this fascinating system might actually be a useful therapeutic drug target for clinical conditions such as hypertension and muscle spasticity. This has been a fascinating 15-year journey in collaboration with Bob who, as well as having an astute scientific mind, is also a great enthusiast, motivator and friend. I hope this exciting and enjoyable journey will continue well into the future.

Functional neuroanatomy of the basal ganglia.

The "basal ganglia" refers to a group of subcortical nuclei responsible primarily for motor control, as well as other roles such as motor learning, executive functions and behaviors, and emotions. Proposed more than two decades ago, the classical basal ganglia model shows how information flows through the basal ganglia back to the cortex through two pathways with opposing effects for the proper execution of movement. Although much of the model has remained, the model has been modified and amplified with the emergence of new data. Furthermore, parallel circuits subserve the other functions of the basal ganglia engaging associative and limbic territories. Disruption of the basal ganglia network forms the basis for several movement disorders. This article provides a comprehensive account of basal ganglia functional anatomy and chemistry and the major pathophysiological changes underlying disorders of movement. We try to answer three key questions related to the basal ganglia, as follows: What are the basal ganglia? What are they made of? How do they work? Some insight on the canonical basal ganglia model is provided, together with a selection of paradoxes and some views over the horizon in the field.

Measurement of medial olivocochlear efferent activity in humans: comparison of different distortion product otoacoustic emission-based paradigms.

OBJECTIVE: To assess the suitability of contralateral suppression (CS) of distortion product otoacoustic emissions (DPOAEs) for measurement of activity of the medial olivocochlear (MOC) efferents. BACKGROUND: The MOC efferent system has been shown to be involved in sound discrimination, selective attention to tones, sound localization, and protection of the cochlea against noise. A great variety of paradigms for measurement of MOC activity by CS of OAE (MOC reflex [MOCR]), has been described. An issue of this approach is the dependence of the CS values on stimulus parameters, especially when DPOAE are used. METHODS: Four different measurement paradigms, which used different combinations of stimulus frequencies and primary tone levels, were applied in 16 human subjects. RESULTS: Mean absolute values of CS were in the range of 1.2 to 2.6 dB. The use of different stimulus parameters produced not only MOCR values of different size-which was expected-but, in many cases, also different relative classifications of the subjects according to their MOCR strength. CONCLUSION: The suppression effects on DPOAE demonstrated in this study reflect MOC activity. However, the new conclusion from our data is that CS of DPOAE measurements, as they were used in this study, may not allow for a consistent quantitative classification of human subjects according to their MOCR strength. This finding concerns interpretation of previous studies using CS of DPOAE and analogous future studies. One future approach may lie in the separation of the DPOAE components to distinguish interference phenomena, which complicate interpretation of CS values.

[Structural basis for the inhibitory function of the parietal cortex efferent systems].

Relative quantitative distribution of all the associative and descending efferent fibers and the ultrastructural organization of the terminals of the parietal cortex areas 5 and 7 in the caudate (NC) and red nucleus (NR) in the cat were analyzed after a local, pointed destruction of the cortex of these areas. The maximal numbers of the associative fibers were found to project to the fundus areas of the motor cortex and to the area of Clare-Bishop; moderate projections were detected to the areas 31, 19 and single degenerating fibers were registered in the areas 1,2, 3a, 3b, 30, and 23. The descending efferents were maximally projecting to NC, NR, reticular nuclei of the thalamus, midbrain, and pons, in all of which, according to the immunocytochemical studies, GABA-ergic terminals are prevalent. On the basis on the electron microscopical studies, it was suggested that the influence of the parietal cortex is mediated by the axo-spinal synapses of the medium shortaxonal spiny cells of the dorsolateral part of NC caput and by the axo-dendritic synapses of Golgi II cells of the parvocellular part of NR. On the basis of the maximal involvement of the fundus areas of the motor cortex, as well as of the inhibitory subcortical (NC) and stem nuclei (NR, reticular nuclei of the thalamus, midbrain, and nuclei pontis), it is suggested that these structures serve as the morphological substrates for the realization of the inhibitory, integrative function of the parietal cortex.

Necessity of the glossopharyngeal nerve in the maintenance of normal intake and ingestive bout size of corn oil by rats.

Recent evidence in the literature suggests that signals carried by the glossopharyngeal nerve (GL), which supplies sensory and parasympathetic innervation of the posterior tongue, might be essential in the maintenance of normal gustatory responses to fat stimuli. Here, we report that GL transection (GLX) significantly decreased corn oil intake and preference in 23-h two-bottle tests relative to sham-operated controls (Sham). Drinking-pattern analysis of corn oil licking revealed that bout size, rather than the number of bouts initiated, was smaller in GLX than Sham rats. We also tested a range of glucose concentrations and found that total licks over daily 23-h sessions significantly decreased in GLX compared with Sham rats, but this difference failed to reach significance when intake or any bout parameter was measured. These results show that the signals in the GL normally contribute to processes involved with corn oil bout termination as opposed to bout initiation. GL-derived signals could potentially provide input to "reward" circuits in the ventral forebrain that could serve to maintain ingestion during a meal or, alternatively, could act at the level of the brain stem to attenuate the inhibitory potency of vagal signals, thus delaying the onset of satiation, or perhaps contribute to a cephalic phase reflex modulation of the gut. Parasympathetic efferents in the GL innervating the von Ebner's glands, which secrete lingual lipase, which is thought to break down corn oil into detectable ligands, could also be playing a role in driving corn oil intake. Whatever the mechanism, an intact GL is clearly necessary in maintaining normal intake of corn oil.

Thalamic afferent and efferent connectivity to cerebral cortical areas with direct projections to identified subgroups of trigeminal premotoneurons in the rat.

The roles of supramedullary brain mechanisms involved in the control of jaw movements are not fully understood. To address this issue, a series of retrograde (Fluorogold, FG) and anterograde (biotinylated dextran amine, BDA) tract-tracing studies were done in rats. At first, we identified projection patterns from defined sensorimotor cortical areas to subgroups of trigeminal premotoneurons that are located in defined brainstem areas. Focal injections of FG into these brainstem areas revealed that the rostralmost part of lateral agranular cortex (rmost-Agl), the rostralmost part of medial agranular cortex (rmost-Agm), and the rostralmost part of primary somatosensory cortex (rmost-S1) preferentially project to brainstem areas containing jaw-closing premotoneurons, jaw-opening premotoneurons and a mixture of both types of premotoneurons, respectively. The thalamic reciprocal connectivities to rmost-Agl, rmost-Agm, and rmost-S1 were then investigated following cortical injections of FG or BDA. We found many retrogradely FG-labeled neurons and large numbers of axons and terminals labeled anterogradely with BDA in the dorsal thalamus mainly on the side ipsilateral to the injection sites. The rmost-Agl had strong connections with the ventral lateral nucleus (VL), ventromedial nucleus (VM), parafascicular nucleus, and posterior nucleus (Po); the rmost-Agm with the ventral anterior nucleus, VL, VM, central lateral nucleus, paracentral nucleus, central medial nucleus, mediodorsal nucleus and Po; and the rmost-S1 with the ventral posteromedial nucleus and Po. The present results suggest that the descending multiple pathways from the cerebral cortex to jaw-closing and jaw-opening premotoneurons have unique functional roles in jaw movement motor control.

Slow build-up of cochlear suppression during sustained contralateral noise: central modulation of olivocochlear efferents?

The strength of the medial olivocochlear (OC) reflex is routinely assayed by measuring suppression of ipsilateral responses such as otoacoustic emissions (OAEs) by a brief contralateral noise, e.g., (Berlin, C.I., Hood, L.J., Cecola, P., Jackson, D.F., Szabo, P. 1993. Does type I afferent dysfunction reveal itself through lack of efferent suppression. Hear. Res. 65, 40-50). Here, we show in anesthetized guinea pigs, that the magnitude of OC-mediated suppression of ipsilateral cochlear responses (i.e., compound actions potentials (CAPs), distortion product (DP) OAEs and round-window noise) slowly builds over 2-3 min during a sustained contralateral noise. The magnitude of this build-up suppression was largest at low ipsilateral stimulus intensities, as seen for suppression measured at contra-noise onset. However, as a function of stimulus frequency, build-up suppression magnitude was complementary to onset suppression, i.e., largest at the lowest and highest frequencies tested. Both build-up and onset suppression were eliminated by cutting the OC bundle. In contrast to "slow effects" of shock-evoked medial OC activity (Sridhar, T.S., Liberman, M.C., Brown, M.C., Sewell, W.F. 1995. A novel cholinergic "slow effect" of efferent stimulation on cochlear potentials in the guinea pig. J. Neurosci. 15, 3667-3678), which are mediated by slow intracellular changes in Ca concentration in OHCs, build-up effects of contralateral noise are immediately extinguished upon OC bundle transection and are likely mediated by central modulation of the response rates in MOC fibers due to the sustained noise. Results suggest that conventional tests of OC reflex strength may underestimate its magnitude in noisy environments.

Amplitude modulation of DPOAEs by acoustic stimulation of the contralateral ear.

CONCLUSION: Otoacoustic emissions generated by outer hair cells (OHCs) are influenced by stimulation of the contralateral ear via a neural pathway involving the olivo-cochlear efferent system. This is often referred to as a contralateral 'suppression reflex', but we suggest that such a term is inappropriate since distortion product otoacoustic emissions (DPOAEs) can be both enhanced and suppressed, and there is continuous modulation with no threshold effects. OBJECTIVE: To characterize the continuous amplitude modulation of DPOAEs by contralateral sound stimulation. MATERIALS AND METHODS: In an animal model (chinchilla), DPOAEs were recorded in real time from one ear during presentation of acoustic stimuli to the opposite ear. RESULTS: DPOAE amplitude is suppressed by an increase in contralateral stimulation, and enhanced by a decrease in same, i.e. the emissions are continuously modulated by activity in the opposite ear. The input-output function shows a linear relationship to this system over a 40-50 dB range of contralateral stimulus levels. After a neural delay time of approximately 25 ms, DPOAE amplitude closely follows contralateral amplitude signals up to modulation frequencies of approximately 20 Hz. Thus, stimuli to one ear continually modulate the OHC system (and therefore the biomechanical amplification) of the contralateral cochlea.

Physiological arousal: a role for hypothalamic systems.

The lateral hypothalamus (LH) has long been known as a homeostasis center of the brain that modulates feeding behavior, arousal and reward. The hypocretins (Hcrts, also called orexins) and melanin-concentrating hormone (MCH) are neuropeptides produced in two intermingled populations of a few thousand neurons in the LH. The Hcrts have a prominent role in regulating the stability of arousal, since Hcrt system deficiency leads to narcolepsy. MCH is an important modulator of energy balance, as MCH system deficiency in mice leads to leanness and increased metabolism. Recently, MCH has been proposed to modulate rapid eye movement sleep in rodents. In this review, we propose a working model of the cross-talk between Hcrt and MCH circuits that may provide an arousal balance system to regulate complex goal-oriented behaviors.

Subclinical dysfunction of cochlea and cochlear efferents in migraine: an otoacoustic emission study.

Otoacoustic emission (OAE) testing enables us to identify the cochlear component of a hearing disorder and to monitor objectively minute changes in cochlear status undetectable by other audiological methods. Contralateral sound-induced suppression is mediated by medial superior olivary complex efferents which induce hyperpolarization counteracting the amplifying effects of outer hair cell (OHC) activity. The aim of this study was to assess functions of cochlea and its efferents in migraine using OAE testing and contralateral suppression of transiently evoked OAEs (TEOAE). Fifty-three migraineurs (106 ears) and 41 healthy subjects (82 ears) were included and pure tone audiometry (PTA), speech discrimination scores (SDS), distortion product OAE (DPOAE), TEOAE and contralateral suppression of TEOAEs were tested. PTA and SDS of migraineurs and controls were not different (P > 0.05). DPOAEs were tested between 1 and 6 kHz and a significant difference was detected only at 5 kHz frequency, where DPOAE amplitudes in migraine with aura (MA) were lower than in controls (P < 0.03). The mean amplitudes of TEOAEs were statistically insignificant between controls and migraine groups. Contralateral sound stimulus induced significant decrease in amplitudes of TEOAE (P = 0.005) in controls. In patients with migraine without aura and MA, mean amplitudes of TEOAEs were not suppressed by contralateral sound stimulus (P > 0.05). As PTA, SDS and DPOAE tests demonstrate normal functioning of inner ear between 1 and 4 kHz, absence of suppression of the TEOAEs by contralateral sound stimulation indicates the presence of dysfunction either in the medial olivocochlear complex in the brainstem or at the synaptic transmission between olivocochlear efferents and OHCs in the cochlea. Disruption in the contralateral suppression may be one of the mechanisms predisposing to the phonophobia symptom associated with migraine headache.

Projections of the nucleus of the basal optic root in pigeons (Columba livia): a comparison of the morphology and distribution of neurons with different efferent projections.

The avian nucleus of the basal optic root (nBOR) is a visual structure involved in the optokinetic response. nBOR consists of several morphologically distinct cell types, and in the present study, we sought to determine if these different cell types had differential projections. Using retrograde tracers, we examined the morphology and distribution of nBOR neurons projecting to the vestibulocerebellum (VbC), inferior olive (IO), dorsal thalamus, the pretectal nucleus lentiformis mesencephali (LM), the contralateral nBOR, the oculomotor complex (OMC) and a group of structures along the midline of the mesencephalon. The retrogradely labeled neurons fell into two broad categories: large neurons, most of which were multipolar rather than fusiform and small neurons, which were either fusiform or multipolar. From injections into the IO, LM, contralateral nBOR, and structures along the midline-mesencephalon small nBOR neurons were labeled. Although there were no differences with respect to the size of the labeled neurons from these injections, there were some differences with the respect to the distribution of labeled neurons and the proportion of multipolar vs. fusiform neurons. From injections into the VbC, the large multipolar cells were labeled throughout nBOR. The only other cases in which these large neurons were labeled were contralateral OMC injections. To investigate if single neurons project to multiple targets we used paired injections of red and green fluorescent retrograde tracers into different targets. Double-labeled neurons were never observed indicating that nBOR neurons do not project to multiple targets. We conclude that individual nBOR neurons have unique projections, which may have differential roles in processing optic flow and controlling the optokinetic response.

Auditory physiology and anatomy of octavolateral efferent neurons in a teleost fish.

Vertebrate hair cell systems receive innervation from efferent neurons in the brain. Here we report the responses of octavolateral efferent neurons that innervate the inner ear and lateral lines in a teleost fish, Dormitator latifrons, to directional linear accelerations, and compare them with the afferent responses from the saccule, the main auditory organ in the inner ear of this species. Efferent neurons responded to acoustic stimuli, but had significantly different response properties than saccular afferents. The efferents produced uniform, omnidirectional responses with no phase-locking. Evoked spike rates increased monotonically with stimulus intensity. Efferents were more broadly tuned and responsive to lower frequencies than saccular afferents, and efferent modulation of the otolithic organs and lateral lines is likely more pronounced at lower frequencies. The efferents had wide dynamic ranges, shallow rate-level function slopes, and low maximum discharge rates. These findings support the role of the efferent innervation of the otolithic organs as part of a general arousal system that modulates overall sensitivity of the peripheral octavolateral organs. In addition, efferent feedback may help unmask biologically relevant directional stimuli, such as those emitted by a predator, prey, or conspecific, by reducing sensitivity of the auditory system to omnidirectional ambient noise.

Age-related changes in the inhibitory response properties of dorsal cochlear nucleus output neurons: role of inhibitory inputs.

Age-related hearing loss frequently results in a loss in the ability to discriminate speech signals, especially in noise. This is attributable, in part, to a loss in temporal resolving power and ability to adjust dynamic range. Circuits in the adult dorsal cochlear nucleus (DCN) have been shown to preserve signal in background noise. Fusiform cells, major DCN output neurons, receive focused glycinergic inputs from tonotopically aligned vertical cells that also project to the ventral cochlear nucleus. Glycine-mediated inhibition onto fusiform cells results in decreased tone-evoked activity as intensity is increased at frequencies adjacent to characteristic frequency (CF). DCN output is thus shaped by glycinergic inhibition, which can be readily assessed in recordings from fusiform cells. Previous DCN studies suggest an age-related loss of markers for glycinergic neurotransmission. The present study postulated that response properties of aged fusiform cells would show a loss of inhibition, resembling conditions observed with glycine receptor blockade. The functional impact of aging was examined by comparing response properties from units meeting fusiform-cell criteria in young and aged rats. Fusiform cells in aged animals displayed significantly higher maximum discharge rates to CF tones than those recorded from young-adult animals. Fusiform cells of aged rats displayed significantly fewer nonmonotonic CF rate-level functions and an age-related change in temporal response properties. These findings are consistent with an age-related loss of glycinergic input, likely from vertical cells, and with findings from other sensory aging studies suggesting a selective age-related decrement in inhibitory amino acid neurotransmitter function.

Effects of efferent acoustic reflex activation on psychoacoustical tuning curves in humans.

CONCLUSIONS: The results show that, in humans, activation of the contralateral EAR makes the PTC narrower at 1 kHz but wider at 4 kHz. These data are consistent with those reported previously in animals and demonstrate that, during medial efferent stimulation in humans, frequency resolution is improved at low frequencies but impaired at high frequencies. OBJECTIVE: To evaluate, in humans, the effect of activation of the contralateral efferent acoustic reflex (EAR) on the psychoacoustical tuning curves (PTCs) recorded for 1- and 4-kHz probe tones. MATERIAL AND METHODS. Ten young (20-30 years) volunteers served as subjects. They had normal hearing (thresholds <20 dB HL in the frequency range 0.25-8 kHz) and a functioning EAR (contralateral suppression of transient-evoked otoacoustic emissions > or = 0.8 dB). Frequency resolution was evaluated using PTCs. PTCs were recorded at 1 and 4 kHz using a simultaneous masking method. Q10 and Q20 were calculated as the ratio between the test frequency and the bandwidth of the PTC at 10 and 20 dB above the tip of the curve, respectively. The EAR was activated with a 40-dB SL contralateral narrow-band noise centered on the characteristic frequency of the PTC (1 or 4 kHz). Q10 and Q20 were measured in the presence and absence of the contralateral noise. RESULTS: Activation of the EAR led to a significant increase (p < 0.001) in Q10 at 1 kHz and a significant decrease (p <0.001) at 4 kHz. Changes in the value of Q20 were not significant.

The effects of body position on distortion-product otoacoustic emission testing.

Otoacoustic emissions are frequently acquired from patients in a variety of body positions aside from the standard, seated orientation. Yet little knowledge is available regarding whether these deviations will produce nonpathological changes to the clinical results obtained. The present study aimed to describe the effects of body position on the distortion-product otoacoustic emissions of 60 normal-hearing adults. With particular attention given to common clinical practice, the Otodynamics ILO292, and the measurement parameters of amplitude, signal-to-noise ratio, and noise were utilized. Significant position-related effects and interactions were revealed for all parameters. Specifically, stronger emissions in the mid frequencies and higher noise levels at the extreme low and high frequencies were produced by testing subjects while lying on their side compared with the seated position. Further analysis of body position effects on emissions is warranted, in order to determine the need for clinical application of position-dependent normative data.

In vivo dynamic ME-MRI reveals differential functional responses of RA- and area X-projecting neurons in the HVC of canaries exposed to conspecific song.

HVC (nidopallial area, formerly known as hyperstriatum ventrale pars caudalis), a key centre for song control in oscines, responds in a selective manner to conspecific songs as indicated by electrophysiology. However, immediate-early gene induction cannot be detected in this nucleus following song stimulation. HVC contains neurons projecting either towards the nucleus robustus archistriatalis (RA; motor pathway) or area X (anterior forebrain pathway). Both RA- and area X-projecting cells show auditory responses. The present study analysed these responses separately in the two types of HVC projection neurons of canaries by a new in vivo approach using manganese as a calcium analogue which can be transported anterogradely and used as a paramagnetic contrast agent for magnetic resonance imaging (MRI). Manganese was stereotaxically injected into HVC and taken up by HVC neurons. The anterograde axonal transport of manganese from HVC to RA and area X was then followed by MRI during approximately 8 h and changes in signal intensity in these targets were fitted to sigmoid functions. Data comparing birds exposed or not to conspecific songs revealed that song stimulation specifically affected the activity of the two types of HVC projection neurons (increase in the sigmoid slope in RA and in its maximum signal intensity in area X). Dynamic manganese-enhanced MRI thus allows assessment of the functional state of specific neuronal populations in the song system of living canaries in a manner reminiscent of functional MRI (but with higher resolution) or of 2-deoxyglucose autoradiography (but in living subjects).

Hypothalamic regulation of pancreatic secretion is mediated by central cholinergic pathways in the rat.

The vago-vagal reflex plays an important role in mediating pancreatic secretion evoked by cholecystokinin and non-cholecystokinin-dependent luminal factors. We hypothesize that the vago-vagal reflex mediating pancreatic secretion in the rat is under central control and regulated by cholinergic pathways in the hypothalamus. To test this hypothesis, we demonstrated that chronic decerebration decreased basal pancreatic enzyme secretion from 318 +/- 12 to 233 +/- 9 mg h-1 and reduced the net increase in pancreatic secretion stimulated by intraduodenal infusion of 5 % peptone and hypertonic NaCl by 54 % and 45 %, respectively. Intracerebroventricular administration of methscopolamine (MSCP, 50 nmol (5 mul)-1), a blood-brain barrier-impermeant cholinergic muscarinic receptor antagonist, evoked results similar to those achieved by chronic decerebration. To localize the sites of action, we demonstrated that microinjection of MSCP (20 nmol) into the lateral hypothalamic nucleus or the paraventricular nucleus resulted in inhibition of both basal pancreatic protein secretion and luminally stimulated pancreatic secretion by 48 % and 52 %, respectively. Intracerebroventricular injection of hemicholinium-3 at doses known to deplete the endogenous ACh store produced similar inhibitory results. In addition, microinjection of ACh (5 pmol) or the muscarinic M1 receptor agonist McN-A-343 (30 ng) into the lateral hypothalamic nucleus increased pancreatic secretion over basal levels by 46 % and 40 %, respectively. Selective lesions of lateral septal cholinergic neurons decreased basal pancreatic secretion and inhibited peptone-induced pancreatic secretion by 30 %. Destruction of the lateral parabrachial nucleus produced a 44 % inhibition of peptone-induced pancreatic section. Finally, microinjection of glutamate into the lateral septum or the lateral parabrachial nucleus stimulated vagal pancreatic efferent nerve firings from a basal level of 0 +/- 0.5 impulses (30 s)-1 to 4.5 +/- 0.5 and 14 +/- 2 impulses (30 s)-1, respectively, and pancreatic protein output increased 50 % and 84 % over basal levels. Administration of MSCP to the paraventricular nucleus eliminated these effects. These observations suggest that cholinergic neurons of the lateral septum and lateral parabrachial nucleus regulate pancreatic secretion. Further, cholinergic input from the lateral parabrachial nucleus to the hypothalamus plays a major role in the modulation of vagal pancreatic efferent nerve activity and pancreatic secretion evoked by the vago-vagal reflex.

Conditional expression in corticothalamic efferents reveals a developmental role for nicotinic acetylcholine receptors in modulation of passive avoidance behavior.

Prenatal nicotine exposure has been linked to attention deficit hyperactivity disorder and cognitive impairment, but the sites of action for these effects of nicotine are still under investigation. High-affinity nicotinic acetylcholine receptors (nAChRs) contain the beta2 subunit and modulate passive avoidance (PA) learning in mice. Using an inducible, tetracycline-regulated transgenic system, we generated lines of mice with expression of high-affinity nicotinic receptors restored in specific neuronal populations. One line of mice shows functional beta2 subunit-containing nAChRs localized exclusively in corticothalamic efferents. Functional, presynaptic nAChRs are present in the thalamus of these mice as detected by nicotine-elicited rubidium efflux assays from synaptosomes. Knock-out mice lacking high-affinity nAChRs show elevated baseline PA learning, whereas normal baseline PA behavior is restored in mice with corticothalamic expression of these nAChRs. In contrast, nicotine can enhance PA learning in adult wild-type animals but not in corticothalamic-expressing transgenic mice. When these transgenic mice are treated with doxycycline in adulthood to switch off nAChR expression, baseline PA is maintained even after transgene expression is abolished. These data suggest that high-affinity nAChRs expressed on corticothalamic neurons during development are critical for baseline PA performance and provide a potential neuroanatomical substrate for changes induced by prenatal nicotine exposure leading to long-term behavioral and cognitive deficits.

Activity of different classes of neurons of the motor cortex during locomotion.

This study examines the activity of different classes of neurons of the motor cortex in the rabbit during two locomotion tasks: a simple (on a flat surface) and a complex (overstepping a series of barriers) locomotion. Four classes of efferent neurons were studied: corticocortical (CC) neurons with ipsilateral projection (CCIs), those with contralateral projection (CCCs), descending corticofugal neurons of layer V (CF5s), and those of layer VI (CF6s). In addition, one class of inhibitory interneurons (SINs) was investigated. CF5 neurons and SINs were the only groups that were strongly active during locomotion. In most of these neurons a clear-cut modulation of discharge in the locomotion rhythm was observed. During simple locomotion, CF5s and SINs were preferentially active in opposite phases of the step cycle, suggesting that SINs contribute to formation of the step-related pattern of CF5s. Transition from simple to complex locomotion was associated with changes of the discharge pattern of the majority of CF5 neurons and SINs. In contrast to CF5 neurons, other classes of efferent neurons (CCI, CCC, CF6) were much less active during both simple and complex locomotion. That suggests that CC interactions, both within a hemisphere (mediated by CCIs) and between hemispheres (mediated by CCCs), as well as corticothalamic interactions via CF6 neurons are not essential for motor coordination during either simple or complex locomotion tasks.