Thalamus & related systems最新文献

Parkinson’s disease (PD) is characterized by nigral degeneration of dopaminergic neurons in the pars compacta of the substantia nigra. Rather than treating only the symptomatic aspects of Parkinson’s disease, one may also consider treatments designed to retard, arrest, or even reverse this degenerative process. Such strategies could include preventive or restorative treatments instead of purely palliative treatments. A recent hypothesis states that glutamate output from the subthalamic nucleus (STN) to the substantia nigra contributes to the neurotoxic process underlying dopaminergic cell death in Parkinson’s disease. Furthermore, high-frequency stimulation (HFS) of the STN inhibits neurons resulting in the suppression of their glutamate output. Experiments in both rats and monkeys provide preliminary data supporting this hypothesis. Kainic acid (KA) lesions of the STN prevent the loss of dopaminergic neurons in the substantia nigra after intrastriatal injection of 6-hydroxydopamine (6-OHDA) in rats, and after systemic administration of MPTP in monkeys. In PD patients, the background level of their disease is evaluated in the off medication/off stimulation state (UPDRS III score), over a period of 5 years. Thirty percent of the patients are stabilized and 18% have persistent improvement of their disease-related impairment. Further experiments are needed, including controlled clinical trials utilizing functional imaging of the dopamine transporters and post-synaptic receptors.

This mini-review considers certain factors related to the developmental decrease in rapid eye movement (REM) sleep, including its timing, its relationship to other developmental changes, factors that may influence its progress and its potential role in brain development. Specifically, we discuss some of the theories proposed for its occurrence and agree with the classic notion that REM sleep is, at least, an active mechanism that may play a role in the maturation of the central nervous system (CNS), specifically contributing to the maturation of thalamocortical pathways. The developmental decrease in REM sleep occurs gradually from birth until after puberty in the human, but in other mammals it is brief and coincides with eye and ear opening and the beginning of massive exogenous activation. This purported role for REM sleep may change to involve a number of other functions with age. We describe recent findings showing that intrinsic morphological and physiological properties as well as serotonergic, n-methyl-d-aspartic acid (NMDA) and kainic acid (KA) synaptic inputs to mesopontine cholinergic neurons change dramatically at this critical period in development, perhaps driving what has been proposed as a REM sleep inhibitory process (RIP). We hypothesize that a dysregulation of this process could result in life-long disturbances in REM sleep drive, leading to hypervigilance or hypovigilance such as that observed in a number of disorders which have a mostly postpubertal age of onset. Finally, we also hypothesize that the role of normal cyclic increases in vigilance, observable during both sleep and waking, may be related, at least in part, to cortical blood flow.

Broad amplitude variability and skewed distributions are characteristic features of quantal synaptic currents (minis) at central synapses. The relative contributions of the various underlying sources are still debated. Through computational models of thalamocortical neurons, we separated intra- from extra-synaptic sources. Our simulations indicate that the external factors of local input resistance and dendritic filtering generate equally small amounts of negatively skewed synaptic variability. The ability of these two factors to reduce positive skew increased as their contribution to variability increased, which in control trials for morphological, biophysical, and experimental parameters never exceeded 10% of the range. With these dendritic factors ruled out, we tested multiple release models, which led to distributions with clearly non-physiological multiple peaks. We conclude that intra-synaptic organization is the primary determinant of synaptic variability in thalamocortical neurons and, due to extra-synaptic mechanisms, is more potent than the data suggested. Thalamortical neurons, especially in rodents, constitute a remarkably favorable system for molecular genetic studies of synaptic variability and its functional consequence.

The anterior thalamic nuclei are a key link in pathways associated with emotions and memory. In the preceding study we found that one of the anterior nuclei, the anterior medial (AM), had particularly robust connections with specific medial prefrontal and orbitofrontal cortices and moderate connections with frontal polar cortices. The goal of this study was to use a direct approach to determine the sources of projections to the AM nucleus from all prefrontal cortices, as well as from temporal structures and the hypothalamic mammillary body, known for their role in distinct aspects of memory and emotion. We addressed this issue with targeted injections of retrograde fluorescent tracers in the AM nucleus to determine its sources of input.

Projection neurons directed to the AM nucleus were found in the deep layers of most prefrontal cortices (layers V and VI), and were most densely distributed in medial areas 24, 32 and 25, orbitofrontal areas 13 and 25, and lateral areas 10 and 46. Most projection neurons were found in layer VI, though in medial prefrontal cortices and dorsal area 9 about a third were found in layer V, a significantly higher proportion than in lateral and orbitofrontal cortices. In the temporal lobe, projection neurons originated mostly from the hippocampal formation (ammonic field CA3 and subicular complex), and the amygdala (basolateral, lateral, and basomedial nuclei). In the hypothalamus, a significant number of neurons in the ipsilateral medial mammillary body projected to the AM nucleus, some of which were positive for calbindin (CB) or parvalbumin (PV), markers expressed, respectively, in “diffuse” and “specific” pathways in the thalamus [Adv. Neurol. 77 (1998a) 49]. As recipient of diverse signals, the AM nucleus is in a key position to link pathways associated with emotions, and may be an important interface for systems associated with retrieval of information from long-term memory in the process of solving problems within working memory. Finally, the internal segment of the globus pallidus (GPi) issued projections to AM, suggesting direct linkage with executive systems through the basal ganglia. The diverse connections of the AM nucleus may help explain the varied deficits in memory and emotions seen in neurodegenerative and psychiatric diseases affecting the anterior thalamic nuclei.

Subthalamic nucleus (STN) neurons have a pivotal role in basal ganglia, as a result of their intrinsic membrane properties, connections within the circuit and glutamatergic nature. Their innate pacemaker activity, consisting of a single-spike tonic mode of discharge, is abolished in the case of hemiballism, profoundly disrupted in the Parkinsonian state and replaced by a regular bursting mode under treatment (high-frequency stimulation, HFS). We propose that control STN activity represents a clock, an internal measure of time allowing the correct automatic execution of learned movements and, in particular, the automatic switch from one movement to the next in a sequential motor pattern. STN neuronal activity would be able to reset the frequency of oscillations of motor thalamo–cortical loops, notably in the γ band.

The anterior thalamic nuclei occupy a central position in pathways associated with emotions and memory [AMA Arch. Neurol. Psychiatry 38 (1937) 725]. The goal of this study was to determine the anatomic interaction of the anterior nuclei with distinct prefrontal cortices that have been implicated in emotion and specific aspects of memory. To address this issue, we investigated the relationship of input and output zones in the anterior thalamic nuclei linking them with functionally distinct orbitofrontal, medial, and lateral prefrontal cortices. We identified input zones by mapping the pattern and topography of terminations of prefrontal axons, and the output zones by mapping projection neurons in the anterior nuclei, after injection of anterograde and bidirectional tracers in distinct prefrontal cortices.

The results showed that the anterior nuclei were preferentially connected with some orbitofrontal and medial prefrontal areas. In contrast, the anterior nuclei had comparatively sparse connections with most lateral prefrontal cortices, with the notable exception of frontal polar cortex, which had moderate but consistent connections with the anterior nuclei. Prefrontal cortices were connected mostly with the anterior medial nucleus, though medial areas 32 and 25 as well as the frontal polar cortex were also connected with the anterior ventral nucleus. The zones of axonal terminations were more expansive than the sites with projection neurons in the anterior nuclei, suggesting extensive influence of feedback projections from prefrontal cortices. The results suggest that the anterior thalamic nuclei may act in concert with orbitofrontal and medial prefrontal cortices in processes underlying emotions and long-term memory, and with the frontal polar cortex in prospective aspects of working memory.

The P50 potential is a midlatency auditory evoked response which is sleep state-dependent, habituates rapidly and is blocked by the muscarinic cholinergic antagonist scopolamine. It is thought to be generated, at least in part, by ascending projections of the reticular activating system. The amplitude of the P50 potential can be used as a measure of level of arousal, while the degree of habituation to repetitive stimulation can be used as a measure of sensory gating. We studied these processes in three conditions which show sleep-wake cycle dysregulation and attentional disturbance, but differ greatly in their etiology, depression, Huntington’s disease and rotation-induced motion sickness. Subjects with depression and rotation-induced motion sickness showed significant decreases in the habituation of the second of paired evoked responses, while Huntington’s disease subjects showed decreased amplitude as well as decreases in the habituation of the second P50 potential. This waveform may represent the manifestation of pre-attentional processes, and may become a useful measure for monitoring the severity, progression and/or remission of disorders which affect these processes.