Central Medial Thalamus Research Articles

Extrasynaptic GABAA receptors in central medial thalamus mediate anesthesia in rats

Neuronal depression in the thalamus underlies anesthetic-induced loss of consciousness, while the precise sub-thalamus nuclei and molecular targets involved remain to be elucidated. The present study investigated the role of extrasynaptic GABAA receptors in the central medial thalamic nucleus (CM) in anesthesia induced by gaboxadol (THIP) and diazepam (DZP) in rats. Local lesion of the CM led to a decrease in the duration of loss of righting reflex induced by THIP and DZP. CM microinjection of THIP but not DZP induced anesthesia. The absence of righting reflex in THIP-treated rats was consistent with the increase of low frequency oscillations in the delta band in the medial prefrontal cortex. CM microinjection of GABAA receptor antagonist SR95531 significantly attenuated the anesthesia induced by systemically-administered THIP, but not DZP. Moreover, the rats with declined expression of GABAA receptor δ-subunit in the CM were less responsive to THIP or DZP. These findings explained a novel mechanism of THIP-induced loss of consciousness and highlighted the role of CM extrasynaptic GABAA receptors in mediating anesthesia.

High-throughput ultrasound neuromodulation in awake and freely behaving rats

Transcranial ultrasound neuromodulation is a promising potential therapeutic tool for the noninvasive treatment of neuropsychiatric disorders. However, the expansive parameter space and difficulties in controlling for peripheral auditory effects make it challenging to identify ultrasound sequences and brain targets that may provide therapeutic efficacy. Careful preclinical investigations in clinically relevant behavioral models are critically needed to identify suitable brain targets and acoustic parameters. However, there is a lack of ultrasound devices allowing for multi-target experimental investigations in awake and unrestrained rodents. We developed a miniaturized 64-element ultrasound array that enables neurointerventional investigations with within-trial active control targets in freely behaving rats. We first characterized the acoustic field with measurements in free water and with transcranial propagation. We then confirmed in vivo that the array can target multiple brain regions via electronic steering, and verified that wearing the device does not cause significant impairments to animal motility. Finally, we demonstrated the performance of our system in a high-throughput neuromodulation experiment, where we found that ultrasound stimulation of the rat central medial thalamus, but not an active control target, promotes arousal and increases locomotor activity.

Paradoxical somatodendritic decoupling supports cortical plasticity during REM sleep.

Rapid eye movement (REM) sleep is associated with the consolidation of emotional memories. Yet, the underlying neocortical circuits and synaptic mechanisms remain unclear. We found that REM sleep is associated with a somatodendritic decoupling in pyramidal neurons of the prefrontal cortex. This decoupling reflects a shift of inhibitory balance between parvalbumin neuron-mediated somatic inhibition and vasoactive intestinal peptide-mediated dendritic disinhibition, mostly driven by neurons from the central medial thalamus. REM-specific optogenetic suppression of dendritic activity led to a loss of danger-versus-safety discrimination during associative learning and a lack of synaptic plasticity, whereas optogenetic release of somatic inhibition resulted in enhanced discrimination and synaptic potentiation. Somatodendritic decoupling during REM sleep promotes opposite synaptic plasticity mechanisms that optimize emotional responses to future behavioral stressors.

Activation of the Central Medial Thalamic Afferent to the Orbitofrontal Cortex Contributes to Successful Reversal Learning

Stress‐related psychiatric disorders, such as major depressive disorder and anxiety disorders, have cognitive symptoms that are not well‐treated by classical antidepressants and cause major detriments to patients’ quality of life. Reversal learning, a form of cognitive flexibility necessary to adapt to a changing environment, is disrupted in stress‐related psychiatric disorders. The orbitofrontal cortex (OFC) mediates reversal learning, and hyperactivity in the OFC is associated with psychiatric disorders in humans. Using a reward‐based discrimination digging task to assess reversal learning in rodents, we have previously reported that chronic stress impairs reversal learning and that inducing long‐term depression in the mediodorsal thalamus to OFC pathway reverses these deficits. However, the circuit‐level mechanisms underlying reversal learning are not well established. Preliminary data using Fos immunohistochemistry, showed a significant decrease in Fos in the lateral OFC following reversal learning, and a significant increase in Fos induction in the central medial thalamus (CM). Converging evidence from other laboratories indicates the CM inhibits the prefrontal cortex. Therefore, we next tested the hypothesis that input to the OFC from the CM, inhibiting the OFC, contributes to successful reversal learning. We used an adeno‐associated virus to deliver an inhibitory (Gi) DREADD or GFP control construct into the CM under the control of the CaMKII promoter, and implanted guide cannulae into the lateral OFC for administration of the DREADD agonist directly at the DREADD‐expressing terminals from the CM. Animals received microinjections of DREADD agonist clozapine‐N‐oxide (300 µM, i.c.) directly preceding the reversal learning task. Activating the Gi DREADD significantly impaired reversal learning, increasing the number of trials it took animals to make six consecutive correct responses. These results suggest that excitatory input from the CM to the OFC is critical for successful reversal learning, indicating a novel role for the CM in cognitive flexibility. Future experiments will investigate the role of thalamic inputs to the OFC in the effects of stress on reversal learning.

The research progress of on the role of central medial thalamus in the sleep anesthesia and awakening

The central medial thalamus is located in the common pathway of the ascending activation system and the descending facilitation pathway. It has extensive projective connections with the cortical and sub-cortical nuclei. More evidences indicated that the central medial thalamus may play an important regulatory role in sleep, anesthesia and awakening. By summarizing the relevant experimental results in recent years, this review introduced the projective relationship and functional classification of the central medial thalamus, highlighted the regulatory role and mechanism of the thalamic central median nucleus in sleep, anesthesia and awakening and discussed the application in promoting the transformation from vegetative state to wakefulness. We finally suggested that the central medial thalamus may be the key nucleus in maintaining the wakefulness and mediating the transition from wake state to sleep and anesthesia state. Key words: Thalamus; Central medial thalamus; Sleep; Anesthesia; Wakefulness

Water diffusion closely reveals neural activity status in rat brain loci affected by anesthesia.

Diffusion functional MRI (DfMRI) reveals neuronal activation even when neurovascular coupling is abolished, contrary to blood oxygenation level—dependent (BOLD) functional MRI (fMRI). Here, we show that the water apparent diffusion coefficient (ADC) derived from DfMRI increased in specific rat brain regions under anesthetic conditions, reflecting the decreased neuronal activity observed with local field potentials (LFPs), especially in regions involved in wakefulness. In contrast, BOLD signals showed nonspecific changes, reflecting systemic effects of the anesthesia on overall brain hemodynamics status. Electrical stimulation of the central medial thalamus nucleus (CM) exhibiting this anesthesia-induced ADC increase led the animals to transiently wake up. Infusion in the CM of furosemide, a specific neuronal swelling blocker, led the ADC to increase further locally, although LFP activity remained unchanged, and increased the current threshold awakening the animals under CM electrical stimulation. Oppositely, induction of cell swelling in the CM through infusion of a hypotonic solution (−80 milliosmole [mOsm] artificial cerebrospinal fluid [aCSF]) led to a local ADC decrease and a lower current threshold to wake up the animals. Strikingly, the local ADC changes produced by blocking or enhancing cell swelling in the CM were also mirrored remotely in areas functionally connected to the CM, such as the cingulate and somatosensory cortex. Together, those results strongly suggest that neuronal swelling is a significant mechanism underlying DfMRI.

Altered activity in the central medial thalamus precedes changes in the neocortex during transitions into both sleep and propofol anesthesia.

How general anesthetics cause loss of consciousness is unknown. Some evidence points toward effects on the neocortex causing "top-down" inhibition, whereas other findings suggest that these drugs act via subcortical mechanisms, possibly selectively stimulating networks promoting natural sleep. To determine whether some neuronal circuits are affected before others, we used Morlet wavelet analysis to obtain high temporal resolution in the time-varying power spectra of local field potentials recorded simultaneously in discrete brain regions at natural sleep onset and during anesthetic-induced loss of righting reflex in rats. Although we observed changes in the local field potentials that were anesthetic-specific, there were some common changes in high-frequency (20-40 Hz) oscillations (reductions in frequency and increases in power) that could be detected at, or before, sleep onset and anesthetic-induced loss of righting reflex. For propofol and natural sleep, these changes occur first in the thalamus before changes could be detected in the neocortex. With dexmedetomidine, the changes occurred simultaneously in the thalamus and neocortex. In addition, the phase relationships between the low-frequency (1-4 Hz) oscillations in thalamic nuclei and neocortical areas are essentially the same for natural sleep and following dexmedetomidine administration, but a sudden change in phase, attributable to an effect in the central medial thalamus, occurs at the point of dexmedetomidine loss of righting reflex. Our data are consistent with the central medial thalamus acting as a key hub through which general anesthesia and natural sleep are initiated.

2009 in Review

2009 in Review

Thalamic Microinjection of Nicotine Reverses Sevoflurane-induced Loss of Righting Reflex in the Rat

Neuronal nicotinic acetylcholine receptors are both potently inhibited by anesthetics and densely expressed in the thalamus. Brain imaging shows that thalamic activity suppression accompanies anesthetic-induced unconsciousness. Therefore, anesthetic-induced unconsciousness may involve direct antagonism of thalamic nicotinic receptors. The authors test this by separately attempting to block or enhance anesthetic-induced loss of righting in rats using intrathalamic microinjections of nicotine or its antagonist. Rats were implanted with a cannula aimed at the thalamus or control locations. A week later, loss of righting was induced using sevoflurane (1.4 +/- 0.2%). A dose-parameter study (n = 35) first identified an optimal intrathalamic nicotine dose associated with arousal. Subsequently, this dose was used to pinpoint the thalamic site mediating the arousal response (n = 107). Finally, sevoflurane righting dose and response specificity were assessed after blocking nicotinic channels with intrathalamic mecamylamine pretreatment (n = 8) before nicotine challenge. Nicotine (150 microg/0.5 microl over 1 min) was the optimal arousal dose, because lower doses (75 microg) were ineffective and higher doses (300 microg) often caused seizures. Nicotine temporarily restored righting and mobility in animals when microinjections involved the central medial thalamus (P < 0.0001, chi-square). Righting occurred despite continued sevoflurane administration. Intrathalamic mecamylamine pretreatment did not lower the sevoflurane dose associated with loss of righting, but prevented the nicotine arousal response. The reversal of unconsciousness found here with intrathalamic microinfusion of nicotine suggests that suppression of the midline thalamic cholinergic arousal system is part of the mechanism by which anesthetics produce unconsciousness.

Changes in brain functional activation during resting and locomotor states after unilateral nigrostriatal damage in rats

To evaluate functional neuronal compensation after partial damage to the nigrostriatal system, we lesioned rats unilaterally in the striatum with 6-hydroxydopamine. Five weeks later, cerebral perfusion was mapped at rest or during treadmill walking using [14C]-iodoantipyrine. Regional CBF-related tissue radioactivity (CBF-TR) was quantified by autoradiography and analyzed by statistical parametric mapping and region-of- interest analysis. Lesions were confirmed by tyrosine hydroxylase immunohistochemistry and changes in rotational locomotor activity.Functional compensations were bilateral and differed at rest and during treadmill walking. Consistent with the classic view of striatopallidal connections, CBF-TR of lesioned compared to sham-lesioned rats increased in the ipsilateral subthalamic nucleus (STN) and internal globus pallidus, and decreased in the striatum and external globus pallidus. Contrary to the classic view, CBF-TR increased in the ipsilateral ventral lateral, ventral anterior thalamus and motor cortex, as well as in the central medial thalamus, midline cerebellum, and contralateral STN.During walking, perfusion decreased in lesioned compared to sham-lesioned rats across the ipsilateral striato-pallidal-thalamic-cortical motor circuit. Compensatory increases were seen bilaterally in the ventromedial thalamus and red nucleus, in the contralateral STN, anterior substantia nigra, subiculum, motor cortex, and in midline cerebellum. Enhanced recruitment of associative sensory areas was noted cortically and subcortically.Future models of compensatory changes after nigrostriatal damage need to address the effects of increased neural activity by residual dopaminergic neurons, interhemispheric interactions and differences between resting and locomotor states. Identification of sites at which functional compensation occurs may define useful future targets for neurorehabilitative or neurorestorative interventions in Parkinson's disease.

Activity of hypothalamic neurons in conscious rats decreased by hyperbaric environment

Single-unit activity of neurons in rat hypothalamus, prefrontal cortex (PFC) and central medial thalamus (CM) was recorded through chronically implanted electrodes. Upon being subjected to 7 atmospheres absolute (ATA) hyperbaric air (709 kPa) environment, about two-thirds of the hypothalamic neurons tested reversibly decreased their firing rate to 71 ± 12% (mean ± SD, n = 25) compared to the precompression control activity, and the remaining one-third did not change their firing rate (100 ± 6%, n = 13). It is suggested that the decrease in firing rate was attributable to increased partial pressure of both oxygen and nitrogen. In contrast to the hypothalamus, the firing rates of most neurons in the PFC and CM did not decrease (99 ± 9% for PFC, 107 ± 12% for CM). In separate acute experiments, 3 out of 5 hypothalamic neurons tested in the isolated forebrain also decreased their firing rates in hyperbaric environment. The results suggest that the hyperbaric air acted directly on the forebrain and depressed more than half of the hypothalamic neurons.