Posterior Medial Thalamus Research Articles

Role of Posterior Medial Thalamus in the Modulation of Striatal Circuitry and Choice Behavior.

The posterior medial (POm) thalamus is heavily interconnected with sensory and motor circuitry and is likely involved in behavioral modulation and sensorimotor integration. POm provides axonal projections to the dorsal striatum, a hotspot of sensorimotor processing, yet the role of POm-striatal projections has remained undetermined. Using optogenetics with slice electrophysiology, we found that POm provides robust synaptic input to direct and indirect pathway striatal spiny projection neurons (D1- and D2-SPNs, respectively) and parvalbumin-expressing fast spiking interneurons (PVs). During the performance of a whisker-based tactile discrimination task, POm-striatal projections displayed learning-related activation correlating with anticipatory, but not reward-related, pupil dilation. Inhibition of POm-striatal axons across learning caused slower reaction times and an increase in the number of training sessions for expert performance. Our data indicate that POm-striatal inputs provide a behaviorally relevant arousal-related signal, which may prime striatal circuitry for efficient integration of subsequent choice-related inputs.

Thalamocortical contributions to working memory processes during the n-back task

Working memory allows individuals to temporally maintain and manipulate information that is no longer accessible from the sensorium. Whereas prior studies have detailed frontoparietal contributions to working memory processes, less emphasis has been placed on subcortical regions, in particular the human thalamus. The thalamus has a complex anatomy that consists of several distinct nuclei, many of which have dense anatomical connectivity with frontoparietal regions, and thus might play an important yet underspecified role for working memory. The goal of our study is to characterize the detailed functional neuroanatomy of the human thalamus and thalamocortical interactions during the n-back task. To that end, we analyzed an n-back fMRI dataset consisting of 395 subjects from the Human Connectome Project (HCP). We found that thalamic nuclei in the anterior, medial, ventral lateral, and posterior medial thalamus showed stronger evoked responses in response to higher working memory load. Activity in most thalamic nuclei were only modulated by working memory load, but not by categorical membership of the memorized stimuli, suggesting that thalamic function supports domain-general processing for working memory. To determine whether thalamocortical interactions contribute to cortical activity for working memory, we employed an activity flow mapping analysis to test whether thalamocortical interactions can predict cortical task activity patterns. In support, this data-driven thalamocortical interaction model explained a significant amount of variance in the observed cortical activity patterns modulated by working memory load. Our results suggest that the anterior, medial, and posterior medial thalamus, and their associated thalamocortical interactions, contribute to the modulations of distributed cortical activity during working memory.

Use of the 3D exoscope for the supracerebellar infratentorial approach in the concorde position: an effective and ergonomic alternative. Illustrative cases

BACKGROUNDThe supracerebellar infratentorial approach provides wide flexibility as a far-reaching corridor to the pineal region, posterior third ventricle, posterior medial temporal lobe, posterolateral mesencephalon, quadrigeminal cistern, and thalamus. Traditionally, the patient is placed in the sitting position, allowing gravity retraction on the cerebellum to widen the supracerebellar operative corridor beneath the tentorium. What this approach gains in anatomical orientation it lacks in surgeon ergonomics, as the sitting position presents technical challenges, forces the surgeon to adopt to an uncomfortable posture while performing the microsurgical dissection/tumor resection under the microscope, and is also associated with an increased risk of venous air embolism.OBSERVATIONSIn this article, the authors present the use of the three-dimensional (3D) exoscope with a standard prone Concorde position as an alternative for the treatment of lesions requiring a supracerebellar infratentorial approach for lesions in the pineal region, posterior third ventricle, and the superior surface of the cerebellar vermis. The authors present four illustrative cases (one pineal cyst, one ependymoma, and two cerebellar metastases) in which this approach provided excellent intraoperative visualization and resulted in good postoperative results. A step-by-step description of our surgical technique is reviewed in detail.LESSONSThe use of the 3D exoscope with the patient in the prone Concorde position is an effective and ergonomically favorable alternative to the traditional sitting position for the treatment of lesions requiring a supracerebellar infratentorial approach. This technique allows improved visualization of deep structures, with a possible decreased risk of potential complications.

Cortical layer 6 control of sensory responses in higher-order thalamus.

Thalamic activity is regulated by corticothalamic feedback from layers 5B and 6. To selectively study the importance of the layer 6 corticothalamic (L6 CT) projection, a transgenic mouse line was used in which layer 6 cells projecting to posterior medial thalamus (POm) were targeted for expression of channelrhodopsin-2. Repetitive optogenetic stimulation of this sub-type of L6 cells caused a rapid adaptation in POm spiking output, but had little effect on the spiking activity in the other cortical layers. L6 photoactivation increased POm spiking to the first, but not to subsequent whisker deflections in a 4 Hz train. A sub-population of L6 CT cells that can cause an initial increase in POm activity, that is not sustained with repetitive stimulation, could indicate that this L6 projection does not modulate ongoing sensory processing, but rather serves to briefly increase POm activity in specific behavioural contexts. Thalamic activity is regulated by corticothalamic feedback from layers 5B and 6. The nature of these feedback systems differs, one difference being that whereas layer 5 provides 'driver' input, the layer 6 input is thought to be 'modulatory'. To selectively study the importance of the layer 6 corticothalamic (L6 CT) projection, a transgenic mouse line was used in which layer 6 cells projecting to posterior medial thalamus (POm) were targeted for expression of channelrhodopsin-2 and in vivo electrophysiology recordings were done in urethane-anaesthetized mice. Pre- and postsynaptic targets were identified using tracing techniques and light-sheet microscopy in cleared intact brains. We find that optogenetic activation of this subtype of L6 CT cells (L6-Drd1) has little effect on cortical activity, but activates POm. Repetitive photoactivation of L6-Drd1 cells evoked a reliable response following every photoactivation, whereas in the connected POm area spiking was only initially increased. The response to repetitive whisker stimulation showed a similar pattern with only an initial increase in whisker-evoked spiking. Furthermore, the increase in whisker-evoked spiking with optogenetic activation of L6-Drd1 cells is additive, rather than multiplicative, causing even cells that in the absence of L6 activation produce relatively few spikes to increase their spiking substantially. We show that layer 6 corticothalamic cells can provide a strong, albeit rapidly depressing, input to POm. This type of cortical L6 activity could be important for rapid gain control in POm, rather than providing a modulation in phase with the whisking cycle.

Anatomically and functionally distinct thalamocortical inputs to primary and secondary mouse whisker somatosensory cortices

Subdivisions of mouse whisker somatosensory thalamus project to cortex in a region-specific and layer-specific manner. However, a clear anatomical dissection of these pathways and their functional properties during whisker sensation is lacking. Here, we use anterograde trans-synaptic viral vectors to identify three specific thalamic subpopulations based on their connectivity with brainstem. The principal trigeminal nucleus innervates ventral posterior medial thalamus, which conveys whisker-selective tactile information to layer 4 primary somatosensory cortex that is highly sensitive to self-initiated movements. The spinal trigeminal nucleus innervates a rostral part of the posterior medial (POm) thalamus, signaling whisker-selective sensory information, as well as decision-related information during a goal-directed behavior, to layer 4 secondary somatosensory cortex. A caudal part of the POm, which apparently does not receive brainstem input, innervates layer 1 and 5A, responding with little whisker selectivity, but showing decision-related modulation. Our results suggest the existence of complementary segregated information streams to somatosensory cortices.

Identification of an Amygdala-Thalamic Circuit That Acts as a Central Gain Mechanism in Taste Perceptions.

Peripheral sources of individual variation in taste intensity perception have been well described. The existence of a central source has been proposed but remains unexplored. Here we used functional magnetic resonance imaging in healthy human participants (20 women, 8 men) to evaluate the hypothesis that the amygdala exerts an inhibitory influence that affects the "gain" of the gustatory system during tasting. Consistent with the existence of a central gain mechanism (CGM), we found that central amygdala response was correlated with mean intensity ratings across multiple tastants. In addition, psychophysiological and dynamic causal modeling analyses revealed that the connection strength between inhibitory outputs from amygdala to medial dorsal and ventral posterior medial thalamus predicted individual differences in responsiveness to taste stimulation. These results imply that inhibitory inputs from the amygdala to the thalamus act as a CGM that influences taste intensity perception.SIGNIFICANCE STATEMENT Whether central circuits contribute to individual variation in taste intensity perception is unknown. Here we used functional magnetic resonance imaging in healthy human participants to identify an amygdala-thalamic circuit where network dynamics and connectivity strengths during tasting predict individual variation in taste intensity ratings. This finding implies that individual differences in taste intensity perception do not arise solely from variation in peripheral gustatory factors.

Connections of Anterior Thalamic Visual Centers in the Leopard Frog, Rana pipiens

The amphibian retina projects to two discrete regions of neuropil in the anterior thalamus: the neuropil of Bellonci and the corpus geniculatum. These retinorecipient areas are encompassed within a larger zone of surrounding neuropil we call the NCZ (for neuropil of Bellonci/corpus geniculatum zone). The NCZ is characterized electrophysiologically by a distinctive tonic oscillatory response to blue light; it appears to be a visual module involved in processing the stationary visual environment. Using horseradish peroxidase (HRP), we mapped the connections of the NCZ. Retrogradely labeled cell bodies are found in: (1) the contralateral anterior thalamus; (2) both retinas; and (3) the posterior medial dorsal thalamus (PMDT). Anterogradely labeled fibers are found in: (1) the contralateral anterior thalamus; (2) the ipsilateral PMDT; (3) the ipsilateral neuropil lateral to the posterior tuberculum in the ventrolateral posterior thalamus; and (4) the ipsilateral anterior medulla. There are no direct connections between the NCZ and the telencephalon, the tectum, or the suprachiasmatic nucleus. Applying HRP to the PMDT, we found that its inputs are limited to the contralateral and ipsilateral NCZ and the contralateral PMDT. Thus, PMDT appears to be a satellite of the NCZ. Blue light elicits tonic oscillatory electrical responses in the PMDT quite similar to the responses to blue light in the NCZ. We discuss how the leopard frog NCZ and the mammalian ventral lateral geniculate nucleus share anatomical and physiological properties.

Cortex dynamically modulates responses of thalamic relay neurons through prolonged circuit-level disinhibition in rat thalamus in vivo.

Cortex actively modulates the responses of thalamic relay neurons through corticothalamic (CT) projections. Here we investigated the temporal precision of CT modulation on sensory responses of relay neurons in rat ventral posterior medial thalamus (VPM) to direction-specific whisker stimuli. CT feedback levels were either augmented by cortical electrical microstimulation or depressed by cortical application of muscimol, a potent agonist of γ-aminobutyric acid A-type (GABAA) receptors. To evaluate the temporal specificity of CT influence, we compared the early (3-10 ms after stimulus onset) and late (10-100 ms) response components of VPM single units to whisker deflections in preferred or nonpreferred directions before and after altering CT feedback levels under urethane anesthesia. The data showed that cortical feedback most strongly affected the late responses of single VPM units to whisker stimulation. That is, cortical stimulation consistently increased the late responses of VPM units in the corresponding (homologous) barreloids to the stimulus direction preferred by neurons in the cortical locus stimulated. However, cortical stimulation could either increase or decrease the early response, depending on whether or not cortical and thalamic loci were tuned to the same direction. Such bidirectional regulation of the early and late VPM responses is consistent with a mechanism of circuit-level disinhibition in vivo. The results support the theory that CT feedback on thalamic sensory responses is mediated by a time-dependent shift of the excitation-inhibition balance in the thalamo-cortico-thalamic loop, such as would occur during sensory feature integration, plasticity, and learning in the awake state.

Barrels XXVII meeting report: Barrels in the monument city

The 27th annual Barrels meeting highlighted the latest advances in this rapidly growing field. The Barrels meeting annually focuses on the role of the posterior medial thalamus in somatosensation, dendritic processing, and the cortical dynamics involved during touch perception. Speakers utilized diverse molecular, physiological, computational techniques to understand the development, sensory processing, and motor commands that are involved with the rodent mystacial vibrissae. The meeting was held Thursday, 13 November through Friday, 14 November 2014 on the Homewood campus of Johns Hopkins University, Baltimore, MD.

Zona Incerta: Target of Electrical Neurostimulation for Neuropathic Pain

Neuropathic pain is a neurological condition caused by damage or disease affecting the central nervous system, which includes the brain, brainstem, and spinal cord. Neuropathic pain commonly manifests as spontaneous, ongoing pain and has various causes including stroke, multiple sclerosis, tumors, epilepsy, brain or spinal cord trauma, and Parkinson’s disease. Because of the limitations and side effects associated with the pharmacological treatment of neuropathic pain, neuroscientists have suggested electrical neurostimulation for pain relief. Electrical neurostimulation procedures such as deep brain stimulation and motor cortex stimulation can regulate neuropathic symptoms in movement disorders, psychiatric diseases, and central pain disorders. However, identifying the appropriate target is necessary to maximize the effectiveness of electrical stimulation. Previous studies have described the incertothalamic pathway for the regulation of nociceptive processing in the thalamus. In this pathway, the inhibitory nucleus zona incerta, a GABAergic nucleus located in the diencephalon, suppresses responses in the posterior medial thalamus. This article will review regulation of neuropathic pain with electrical neurostimulation, focusing on the antinociceptive effects of zona incerta activation.

Skew deviation: clinical updates for ophthalmologists.

This article discusses the current approach in diagnosing skew deviation, as well as recent findings in the lesion localization. Skew deviation can be defined as vertical misalignment of the eyes that does not map to any of cyclovertical muscles, in association with neurologic symptoms and signs and with posterior fossa lesion. It can be differentiated from trochlear nerve palsy by the direction of ocular torsion and the change in the degree of vertical deviation with upright and supine head position. It is commonly caused by ischemia of the posterior paramedian pons, medial thalamus, or cerebellum. Other less common mechanism being demyelinating lesion, mass effect, infection, hemorrhage, or intracranial hypertension. When the vestibular nuclei are involved, skew deviation may occur with acute vestibular syndrome. Ground-in or Fresnel prism may alleviate diplopia in relatively small vertical deviation; however, patient with larger deviation or with the presence of ocular torsion may benefit from surgery of the cyclovertical muscles. Skew deviation can be appropriately diagnosed from the nature of the ocular torsion and the vertical deviation, along with the presence of lesion involving posterior paramedian pons and/or medial thalamus.

Thalamic metabolic alterations with cognitive dysfunction in idiopathic trigeminal neuralgia: a multivoxel spectroscopy study.

Although abnormalities in metabolite compositions in the thalamus are well described in patients with idiopathic trigeminal neuralgia (ITN), differences in distinct thalamic subregions have not been measured with proton magnetic resonance spectroscopy ((1)H-MRS), and whether there are correlations between thalamic metabolites and cognitive function still remain unknown. Multivoxel MRS was recorded to investigate the metabolic alterations in the thalamic subregions of patients with ITN. The regions of interest were localized in the anterior thalamus (A-Th), intralaminar portion of the thalamus (IL-Th), posterior lateral thalamus (PL-Th), posterior medial thalamus (PM-Th), and medial and lateral pulvinar of the thalamus (PuM-Th and PuL-Th). The N-acetylaspartate to creatine (NAA/Cr) and choline to creatine (Cho/Cr) ratios were measured in the ITN and control groups. Scores of the visual analogue scale (VAS) and the Montreal Cognitive Assessment (MoCA) were analyzed to correlate with the neuroradiological findings. The NAA/Cr ratio in the affected side of PM-Th and PL-Th in ITN patients was statistically lower than that in the corresponding regions of the thalamus in controls. The NAA/Cr ratio in the affected PM-Th was negatively associated with VAS and disease duration. Furthermore, decreases of NAA/Cr and Cho/Cr were detected in the affected side of IL-Th, and lower Cho/Cr was positively correlated with MoCA values in the ITN group. Our result of low level of NAA/Cr in the affected PM-Th probably serves as a marker of the pain-rating index, and decreased Cho/Cr in IL-Th may be an indicator of cognitive disorder in patients with ITN.

Neuropathology in sensory, but not motor, brainstem nuclei of the rat whisker circuit after diffuse brain injury

Neurological dysfunction after traumatic brain injury (TBI) is associated with pathology in cortical, subcortical, and brainstem nuclei. Our laboratory has reported neuropathology and microglial activation in the somatosensory barrel cortex (S1BF) and ventral posterior medial thalamus (VPM) after diffuse TBI in the rat, which correlated with post-injury whisker sensory sensitivity. The present study extends our previous work by evaluating pathology in whisking-associated sensory and motor brainstem nuclei. Brains from adult, male rats were recovered over 1 month after midline fluid percussion or sham injury. The principal trigeminal nucleus (PrV, sensory nucleus) and facial nucleus (VIIN, motor nucleus) were examined for neuropathology (silver histochemistry) and microglial activation (Iba1). Significant neuropathology in PrV was evident at 2 and 7 days post-injury compared to sham. Iba1-labeled microglia showed swollen somata and thickened processes over 1 month post-injury. In contrast, the VIIN showed non-significant neuropathology and reduced labeling of activated Iba1 microglia over 1 month post-injury. Together with our previous data, neuropathology and neuroinflammation in the whisker somatosensory pathway may contribute to post-injury sensory sensitivity more than the motor pathway. Whether these findings are direct results of the mechanical injury or consequences of progressive degeneration remains to be determined.

Evidence for a regional specificity in the density and distribution of noradrenergic varicosities in rat cortex.

The brainstem nucleus locus coeruleus (LC) is the sole source of norepinephrine (NE)-containing fibers in the mammalian cortex. Previous studies suggest that the density of noradrenergic fibers in rat is relatively uniform across cortical regions and that cells in the nucleus discharge en masse. This implies that activation of the LC results in equivalent release of NE throughout the cortex. However, it is possible that there could be differences in the density of axonal varicosities across regions, and that these differences, rather than a difference in fiber density, may contribute to the regulation of NE efflux. Quantification of dopamine β-hydroxylase (DβH)-immunostained varicosities was performed on several cortical regions and in the ventral posterior medial (VPM) thalamus by using unbiased sampling methods. The density of DβH varicosities is greater in the prefrontal cortex than in motor, somatosensory, or piriform cortices, greater in superficial than in deep layers of cortex, and greater in the VPM than in the somatosensory cortex. Our results provide anatomical evidence for non-uniform release of NE across functionally discrete cortical regions. This morphology may account for a differential, region-specific, impact of LC output on different cortical areas.

Hypersensitive glutamate signaling correlates with the development of late-onset behavioral morbidity in diffuse brain-injured circuitry.

In diffuse brain-injured rats, robust sensory sensitivity to manual whisker stimulation develops over 1 month post-injury, comparable to agitation expressed by brain-injured individuals with overstimulation. In the rat, whisker somatosensation relies on thalamocortical glutamatergic relays between the ventral posterior medial (VPM) thalamus and barrel fields of somatosensory cortex (S1BF). Using novel glutamate-selective microelectrode arrays coupled to amperometry, we test the hypothesis that disrupted glutamatergic neurotransmission underlies the whisker sensory sensitivity associated with diffuse brain injury. We report hypersensitive glutamate neurotransmission that parallels and correlates with the development of post-traumatic sensory sensitivity. Hypersensitivity is demonstrated by significant 110% increases in VPM extracellular glutamate levels, and 100% increase in potassium-evoked glutamate release in the VPM and S1BF, with no change in glutamate clearance. Further, evoked glutamate release showed 50% greater sensitivity to a calcium channel antagonist in brain-injured over uninjured VPM. In conjunction with no changes in glutamate transporter gene expression and exogenous glutamate clearance efficiency, these data support a presynaptic origin for enduring post-traumatic circuit alterations. In the anatomically-distinct whisker circuit, the injury-induced functional alterations correlate with the development of late-onset behavioral morbidity. Effective therapies to modulate presynaptic glutamate function in diffuse-injured circuits may translate into improvements in essential brain function and behavioral performance in other brain-injured circuits in rodents and in humans.

Effects of Repeated 3,4-Methylenedioxymethamphetamine Administration on Neurotransmitter Efflux and Sensory-Evoked Discharge in the Ventral Posterior Medial Thalamus

3,4-Methylenedioxymethamphetamine (MDMA) is known to enhance tactile sensory perception, an effect that contributes to its popularity as a recreational drug. The neurophysiological basis for the effects of MDMA on somatosensation are unknown. However, MDMA interactions with the serotonin transporter (SERT) and subsequent enhancement of serotonin neurotransmission are well known. The rat trigeminal somatosensory system receives serotonergic afferents from the dorsal raphe nucleus. Because these fibers express SERT, they should be vulnerable to MDMA-induced effects. We found that administration of a challenge injection of MDMA (3 mg/kg i.p.) after repeated MDMA treatment (3 mg/kg per day for 4 days) elicits both serotonin and norepinephrine efflux in the ventral posterior medial (VPM) thalamus of Long-Evans hooded rats, the main relay along the lemniscal portion of the rodent trigeminal somatosensory pathway. We evaluated the potential for repeated MDMA administration to modulate whisker-evoked discharge of individual neurons in this region. After surgically implanting stainless steel eight-wire multichannel electrode bundles, we recorded spike train activity of single cells while activating the whisker pathway using a piezoelectric mechanical stimulator. We found that repeated MDMA administration increased the spontaneous firing rate but reduced both the magnitude and duration of whisker-evoked discharge in individual VPM thalamic neurons. The time course of drug action on neuronal firing patterns was generally consistent with fluctuations in neurotransmitter efflux as shown from our microdialysis studies. On the basis of these results, we propose that single use and repeated administration of MDMA may "distort," rather than enhance, tactile experiences in humans, in part, by disrupting normal spike firing patterns through somatosensory thalamic relay circuits.

Phasic and Tonic Patterns of Locus Coeruleus Output Differentially Modulate Sensory Network Function in the Awake Rat

Neurons of the nucleus locus coeruleus (LC) discharge with phasic bursts of activity superimposed on highly regular tonic discharge rates. Phasic bursts are elicited by bottom-up input mechanisms involving novel/salient sensory stimuli and top-down decision making processes; whereas tonic rates largely fluctuate according to arousal levels and behavioral states. Although it is generally believed that these two modes of activity differentially modulate information processing in LC targets, the unique role of phasic versus tonic LC output on signal processing in cells, circuits, and neural networks of waking animals is not well understood. In the current study, simultaneous recordings of individual neurons within ventral posterior medial thalamus and barrel field cortex of conscious rats provided evidence that each mode of LC output produces a unique modulatory impact on single neuron responsiveness to sensory-driven synaptic input and representations of sensory information across ensembles of simultaneously recorded cells. Each mode of LC activation specifically modulated the relationship between sensory-stimulus intensity and the subsequent responses of individual neurons and neural ensembles. Overall these results indicate that phasic versus tonic modes of LC discharge exert fundamentally different modulatory effects on target neuronal circuits within the rodent trigeminal somatosensory system. As such, each mode of LC output may differentially influence signal processing as a means of optimizing behaviorally relevant neural computations within this sensory network. Likely the ability of the LC system to differentially regulate neural responses and local circuit operations according to behavioral demands extends to other brain regions including those involved in higher cognitive functions.

Effects of Yokukansan, a Traditional Japanese Medicine, on Memory Disturbance and Behavioral and Psychological Symptoms of Dementia in Thiamine-Deficient Rats

Effects of yokukansan (TJ-54) on memory disturbance and behavioral and psychological symptoms of dementia (BPSD) were investigated in thiamine-deficient (TD) rats which were produced by feeding a TD diet for 37 d. Daily oral administration of TJ-54 (0.5, 1.0 g/kg) ameliorated the memory disturbance, anxiety-like behavior, the increase in aggressive behaviors, the decrease in social behaviors, and several neurological symptoms including opisthotonus observed in TD rats, in a dose-dependent manner. In addition, histopathological examinations showed that TJ-54 inhibited the degeneration of neuronal and astroglial cells in the brain stem, hippocampus and cortex in TD rats. Microdialysis experiments showed that TJ-54 inhibited extracellular glutamate rise in the ventral posterior medial thalamus in TD rats. These results suggest that TJ-54 possesses the preventive or progress inhibitive effect against the development of memory disturbance and BPSD-like behaviors induced by the degeneration of neuronal and astroglial cells resulting from TD. TJ-54 may inhibit glutamate-mediated excitotoxicity as one of mechanisms.

Motor modulation of afferent somatosensory circuits

A prominent feature of thalamocortical circuitry in sensory systems is the extensive and highly organized feedback projection from the cortex to the thalamic neurons that provide stimulus-specific input to the cortex. In lightly sedated rats, we found that focal enhancement of motor cortex activity facilitated sensory-evoked responses of topographically aligned neurons in primary somatosensory cortex, including antidromically identified corticothalamic cells; similar effects were observed in ventral posterior medial thalamus (VPm). In behaving rats, thalamic responses were normally smaller during whisking but larger when signal transmission in brainstem trigeminal nuclei was bypassed or altered. During voluntary movement, sensory activity may be globally suppressed in the brainstem, whereas signaling by cortically facilitated VPm neurons is simultaneously enhanced relative to other VPm neurons receiving no such facilitation.

MDMA (3,4-Methylenedioxymethamphetamine)-Mediated Distortion of Somatosensory Signal Transmission and Neurotransmitter Efflux in the Ventral Posterior Medial Thalamus

MDMA (3,4-methylenedioxymethamphetamine, Ecstasy) is reported to enhance tactile sensory perception, an effect that is believed to contribute to its popularity as a recreational drug. To date, no literature exists that addresses the neurophysiological mechanisms underlying the effects of MDMA on somatosensation. However, MDMA interactions with the serotonin transporter protein (SERT) are well known. The rat trigeminal somatosensory system has been studied extensively and receives serotonergic afferents from the dorsal raphe nucleus. Given that these fibers express SERT, they should be vulnerable to MDMA-induced effects. We found that short-term low-dose MDMA administration (3 mg/kg i.p.) led to a significant increase in 5-hydroxytryptamine (5-HT) efflux in the ventral posterior medial (VPM) thalamus, the main relay along the lemniscal portion of the rodent trigeminal somatosensory pathway. We further evaluated the potential for MDMA to modulate whisker-evoked discharge (WED) of individual neurons in this region. After surgically implanting stainless steel 8-wire multichannel electrode bundles, we recorded spike train activity from single cells of halothane-anesthetized rats while mechanically activating the whisker pathway. We found that short-term low-dose MDMA (3 mg/kg i.p.) increased the spontaneous firing rate but reduced the magnitude and duration of WED in individual VPM thalamic neurons. It is noteworthy that the time course of drug action on neuronal firing patterns was generally consistent with increased 5-HT efflux as shown from our microdialysis studies. Based on these results, we propose the working hypothesis that MDMA may "distort" rather than enhance tactile experiences in humans, in part, by disrupting normal spike firing patterns through somatosensory thalamic relay circuits.