Journal of Neuroscience

An inherited neurological disorder characterized by sustained twisting movements during waking has been discovered in Sprague-Dawley rats. The mutation follows an autosomal recessive pattern of inheritance and has been named dystonic (dt). The rat mutants are indistinguishable from normal littermates in open field behavior and climbing activity prior to postnatal days 9 to 10. Clinical signs begin to appear on day 10 and include twisting of the axial musculature, hyperflexion of the trunk, self-clasping of forelimbs and hindlimbs, and poor placement of the limbs during locomotion. No morphological lesions of neural or non- neural tissues have been observed with routine light microscopy. Dystonic rats demonstrate significantly elevated cerebellar norepinephrine levels, although levels in other terminal fields of the locus ceruleus are similar to those of normal littermates. No differences in the pattern or density of noradrenergic innervation were apparent in cerebellar tissue from dt rats examined with histochemical fluorescence techniques. These mutants were less sensitive than unaffected littermates to the akinesic effects of the dopamine blocker haloperidol. However, striatal dopamine levels were not reliably different from normal in dt rats, and their response to the movement- stimulating effects of apomorphine appeared normal. These findings suggest the presence of biochemical disturbances in the extrapyramidal system of dt rats. The dt rat may provide a useful model for human dystonia musculorum deformans.

Narcolepsy is a genetically determined disorder of sleep characterized by excessive daytime sleepiness and abnormal manifestations of REM sleep that affects both humans and animals. Although its exact pathophysiologic mechanisms remain undetermined, recent experiments have demonstrated that in both humans and canines, susceptibility genes are linked with immune-related genes. A striking difference, however, is that the genes thought to be involved in the human pathology are autosomal dominant, whereas canine narcolepsy in Dobermans is transmitted as a single autosomal recessive gene with full penetrance (canarc-1). In this study, we have examined the development of narcoleptic symptoms in homozygous narcoleptic, heterozygous, and control Dobermans. Animals were behaviorally observed until 5 months of age and then treated at weekly intervals with cataplexy-inducing compounds that act on cholinergic or monoaminergic systems (alone and in combination). Our data indicate that cataplexy can be induced in 6- month-old asymptomatic heterozygous animals, but not in control canines, with a combination of drugs that act on the monoaminergic and cholinergic systems. This demonstrates that disease susceptibility may be carried by heterozygosity at the canarc-1 locus. Our data further suggest that cataplexy, a model of REM sleep atonia, is centrally regulated by a balance of activity between cholinergic and monoaminergic neurons.

We describe a novel slow oscillation in intracellular recordings from cortical association areas 5 and 7, motor areas 4 and 6, and visual areas 17 and 18 of cats under various anesthetics. The recorded neurons (n = 254) were antidromically and orthodromically identified as corticothalamic or callosal elements receiving projections from appropriate thalamic nuclei as well as from homotopic foci in the contralateral cortex. Two major types of cells were recorded: regular- spiking (mainly slow-adapting, but also fast-adapting) neurons and intrinsically bursting cells. A group of slowly oscillating neurons (n = 21) were intracellularly stained and found to be pyramidal-shaped cells in layers III-VI, with luxuriant basal dendritic arbors. The slow rhythm appeared in 88% of recorded neurons. It consisted of slow depolarizing envelopes (lasting for 0.8–1.5 sec) with superimposed full action potentials or presumed dendritic spikes, followed by long- lasting hyperpolarizations. Such sequences recurred rhythmically at less than 1 Hz, with a prevailing oscillation between 0.3 and 0.4 Hz in 67% of urethane-anesthetized animals. While in most neurons (approximately 70%) the repetitive spikes superimposed on the slow depolarization were completely blocked by slight DC hyperpolarization, 30% of cells were found to display relatively small (3–12 mV), rapid, all-or-none potentials after obliteration of full action potentials. These fast spikes were suppressed in an all-or-none fashion at Vm more negative than -90 mV. The depolarizing envelope of the slow rhythm was reduced or suppressed at a Vm of -90 to -100 mV and its duration was greatly reduced by administration of the NMDA blocker ketamine. In keeping with this action, most (56%) neurons recorded in animals under ketamine and nitrous oxide or ketamine and xylazine anesthesia displayed the slow oscillation at higher frequencies (0.6–1 Hz) than under urethane anesthesia (0.3–0.4 Hz). In 18% of the oscillating cells, the slow rhythm mainly consisted of repetitive (15–30 Hz), relatively short-lasting (15–25 msec) IPSPs that could be revealed by bringing the Vm at more positive values than -70 mV. The long-lasting (approximately 1 sec) hyperpolarizing phase of the slow oscillation was best observed at the resting Vm and was reduced at about -100 mV. Simultaneous recording of another cell across the membrane demonstrated synchronous inhibitory periods in both neurons. Intracellular diffusion of Cl- or Cs+ reduced the amplitude and/or duration of cyclic long- lasting hyperpolaryzations.(ABSTRACT TRUNCATED AT 400 WORDS)

One of the functions of the excitatory subthalamic nucleus (STN) is to relay cortical activity to other basal ganglia structures. The response of the STN to cortical input is shaped by inhibition from the reciprocally connected globus pallidus (GP). To examine the activity in the STN–GP network in relation to cortical activity, we recorded single and multiple unit activity in STN and/or GP together with cortical electroencephalogram in anesthetized rats during various states of cortical activation.

During cortical slow-wave activity (SWA), STN and GP neurons fired bursts of action potentials at frequencies that were similar to those of coincident slow (∼1 Hz) and spindle (7–14 Hz) cortical oscillations. Spontaneous or sensory-driven global activation was associated with a reduction of SWA and a shift in STN–GP activity from burst- to tonic- or irregular-firing. Rhythmic activity in STN and GP neurons was lost when the cortex was inactivated by spreading depression and did not resume until SWA had recovered.

Although rhythmic STN–GP activity was correlated with SWA, the phase relationships of activities of neurons within the STN and GP and between the nuclei were variable. Even when neurons displayed synchronous bursting activity, correlations on the millisecond time scale, which might indicate shared synaptic input, were not observed.

These data indicate that (1) STN and GP activity is intimately related to cortical activity and hence the sleep–wake cycle; (2) rhythmic oscillatory activity in the STN–GP network in disease states may be driven by the cortex; and (3) activity of the STN–GP network is regulated in space in a complex manner.

Exposure to sound of sufficient duration and level causes permanent damage to the peripheral auditory system, which results in the reorganization of the cortical tonotopic map. The changes are such that neurons with pre-exposure tuning to frequencies in the hearing loss range now become tuned to frequencies near the near-normal lower boundary of the hearing loss range, which thus becomes over represented. However, cats exposed to a traumatizing noise and immediately thereafter placed for a few weeks in an enriched acoustic environment presented a much-restricted hearing loss compared with similarly exposed cats that were placed for the same time in a quiet environment. The enriched environment spectrally matched the expected hearing loss range and was ∼40 dB above the level of the expected hearing loss. The hearing loss in the quiet environment-reared cats ranged from 6 to 32 kHz with the largest loss (on average, 40 dB) ranging from 24 to 32 kHz. In contrast, the hearing loss in the enriched-environment cats was restricted to 6-8 kHz at a level of, on average, 35 dB and with 16-32 kHz having normal thresholds. Despite the remaining hearing loss for the enriched-environment cats in the 6-8 kHz range, plastic tonotopic map changes in primary auditory cortex could no longer be demonstrated, suggesting that the enriched acoustic environment prevents this reorganization. This finding has implications for the treatment of hearing disorders, such as tinnitus, that have been linked to cortical tonotopic map reorganization.

A slow oscillation (< 1 Hz) has recently been described in intracellular recordings from the neocortex and thalamus (Steriade et al., 1993c-e). The aim of the present study was to determine the phase relations between cortical and thalamic neuronal activities during the slow EEG oscillation. Intracellular recordings were performed in anesthetized cats from neurons in motor and somatosensory cortical areas, the rostrolateral sector of the reticular (RE) thalamic nucleus, and thalamocortical (TC) cells from ventrolateral (VL) nucleus. The EEG was used as time reference for alignment of activities in different, simultaneously recorded neurons, including dual impalements of cortical cells as well as cortical and TC cells. The spontaneous EEG oscillation was characterized by slowly recurring (0.3–0.9 Hz) sequences of surface- positive (depth-negative) sharp deflections, often followed by oscillatory activity within the frequency range of sleep spindles (7–14 Hz) or at faster frequencies. Cortical and RE cells were similarly hyperpolarized during the depth-positive EEG waves and were depolarized during the depth-negative EEG deflections. In many instances, the cell depolarization was associated with oscillations at the spindle frequency or with tonic firing at rates related to the level of depolarization. TC neurons were hyperpolarized during the depth- positive EEG waves and displayed a series of IPSPs, at the spindle frequencies, during the depth-negative EEG waves. Depending on the membrane potential (Vm), TC cells could fire spike bursts at the onset of the EEG depth-negativity, or their firing could be delayed by subsequent IPSPs. The sequence of spontaneous EEG and cellular events described above also characterized the responses to cortical and thalamic stimulation. Simultaneous intracellular recordings of pairs of cortical cells or cortical and TC cells showed that spontaneous transitions from less synchronized to more synchronized EEG states were marked by a simultaneous hyperpolarization, coincident with an overt depth-positive EEG wave. We conclude that during low-frequency oscillatory states, characteristic of slow-wave sleep, neocortical and thalamic neurons display phase relations that are restricted to narrow time windows, and that synchronization results from a generalized inhibitory phenomenon. Moreover, EEG synchronization is reflected as active inhibition in TC neurons. That this pattern is also present in states of hypersynchronization, such as seizure activity, is shown in the following paper (Steriade and Contreras, 1994).

Covertly directing visual attention toward a spatial location in the absence of visual stimulation enhances future visual processing at the attended position. The neuronal correlates of these attention shifts involve modulation of neuronal “baseline” activity in early visual areas, presumably through top-down control from higher-order attentional systems. We used electroencephalography to study the largely unknown relationship between these neuronal modulations and behavioral outcome in an attention orienting paradigm. Covert visuospatial attention shifts to either a left or right peripheral position in the absence of visual stimulation resulted in differential modulations of oscillatory α-band (8–14 Hz) activity over left versus right posterior sites. These changes were driven by varying degrees of α-decreases being maximal contralateral to the attended position. When expressed as a lateralization index, these α-changes differed significantly between attention conditions, with negative values (α_right < α_left) indexing leftward and more positive values (α_left ≤ α_right) indexing rightward attention. Moreover, this index appeared deterministic for processing of forthcoming visual targets. Collapsed over trials, there was an advantage for left target processing in accordance with an overall negative bias in α-index values. Across trials, left targets were detected most rapidly when preceded by negative index values. Detection of right targets was fastest in trials with most positive values. Our data indicate that collateral modulations of posterior α-activity, the momentary bias of visuospatial attention, and imminent visual processing are linked. They suggest that the momentary direction of attention, predicting spatial biases in imminent visual processing, can be estimated from a lateralization index of posterior α-activity.