Higher-Order Thalamic Encoding of Somatosensory Patterns and Bilateral Events.

The function of the higher-order sensory thalamus remains unclear. Here, the posterior medial (POm) nucleus of the thalamus was examined by in vivo extracellular recordings in anesthetized rats across a variety of contralateral, ipsilateral, and bilateral whisker sensory patterns. We found that POm was highly sensitive to multiwhisker stimuli involving diverse spatiotemporal interactions. Accurate increases in POm activity were produced during the overlapping time between spatial signals reflecting changes in the spatiotemporal structure of sensory patterns. In addition, our results showed for first time that POm was also able to respond to tactile stimulation of ipsilateral whiskers. This finding challenges the notion that the somatosensory thalamus only computes unilateral stimuli. We found that POm also integrates signals from both whisker pads and described how this integration is generated. Our results showed that ipsilateral activity reached one POm indirectly from the other POm and demonstrated a transmission of sensory activity between both nuclei through a functional POm-POm loop formed by thalamocortical, interhemispheric, and corticothalamic projections. The implication of different cortical areas was investigated revealing that S1 plays a central role in this POm-POm loop. Accordingly, the subcortical and cortical inputs allow POm but not the ventral posteromedial thalamic nucleus (VPM) to have sensory information from both sides of the body. This finding is in agreement with the higher-order nature of POm and can be considered to functionally differentiate and classify these thalamic nuclei. A possible functional role of these higher-order thalamic patterns of integrated activity in brain function is discussed.

Insulin-like growth factor I modulates sleep through hypothalamic orexin neurons.

Although sleep disturbances are common co-morbidities of metabolic diseases, the underlying processes linking both are not yet fully defined. Changes in the duration of sleep are paralleled by changes in the levels of insulin-like growth factor-I (IGF-I), an anabolic hormone that shows a circadian pattern in the circulation and activity-dependent entrance in the brain. However, the specific role, if any, of IGF-I in this universal homeostatic process remains poorly understood. We now report that the activity of orexin neurons, a discrete cell population in the lateral hypothalamus that is involved in the circadian sleep/wake cycle and arousal, is modulated by IGF-I. Furthermore, mice with blunted IGF-I receptor activity in orexin neurons have lower levels of orexin in the hypothalamus, show altered electro-corticographic patterns with predominant slow wave activity, and reduced onset-sleep latency. Collectively, these results extend the role in the brain of this pleiotropic growth factor to shaping sleep architecture through the regulation of orexin neurons. We speculate that poor sleep quality associated to diverse conditions may be related to disturbed brain IGF-I input to orexin neurons.

Ocoxin Modulates Cancer Stem Cells and M2 Macrophage Polarization in Glioblastoma.

Glioblastoma (GBM) is the most common and devastating primary brain tumor. The presence of cancer stem cells (CSCs) has been linked to their therapy resistance. Molecular and cellular components of the tumor microenvironment also play a fundamental role in the aggressiveness of these tumors. In particular, high levels of hypoxia and reactive oxygen species participate in several aspects of GBM biology. Moreover, GBM contains a large number of macrophages, which normally behave as immunosuppressive tumor-supportive cells. In fact, the presence of both, hypoxia and M2-like macrophages, correlates with malignancy and poor prognosis in gliomas. Antioxidant agents, as nutritional supplements, might have antitumor activity. Ocoxin® oral solution (OOS), in particular, has anti-inflammatory and antioxidant properties, as well as antitumor properties in several neoplasia, without known side effects. Here, we describe how OOS affects stem cell properties in certain GBMs, slowing down their tumor growth. In parallel, OOS has a direct effect on macrophage polarization in vitro and in vivo, inhibiting the protumoral features of M2 macrophages. Therefore, OOS could be a feasible candidate to be used in combination therapies during GBM treatment because it can target the highly resilient CSCs as well as their supportive immune microenvironment, without adding toxicity to conventional treatments.

Medial Prefrontal Cortical Modulation of Whisker Thalamic Responses in Anesthetized Rats.

The medial prefrontal cortex (mPFC) has been implicated in novelty detection and attention. We studied the effect of mPFC electrical stimulation on whisker responses recorded in the ventroposterior medial thalamic nucleus (VPM), the posterior thalamic nucleus (POm) and the primary somatosensory (S1) cortex in urethane anesthetized rats. Field potentials and unit recordings were performed in the VPM or POm thalamic nuclei, in S1 cortex, and in the Zona Incerta (ZI). Somatosensory evoked potentials were elicited by whisker deflections. Current pulses were delivered by bipolar stimulating electrodes aimed at the prelimbic (PL) or infralimbic (IL) areas of mPFC. PL train stimulation (50 Hz, 500 ms) induced a facilitation of whisker responses in the VPM nucleus that lasted minutes and a short inhibition in the POm nucleus. IL stimulation induced a facilitation of whisker responses in both VPM and POm nuclei. Facilitation was due to corticofugal projections because it was reduced after S1 cortical inactivation with lidocaine, and by activation of NMDA glutamatergic receptors because it was blocked by APV. Paired stimulation of mPFC and whiskers revealed an inhibitory effect at short intervals (<100 ms), which was mediated by ZI inhibitory neurons since PL stimulation induced response facilitation in the majority of ZI neurons (42%) and muscimol injection into ZI nucleus reduced inhibitory effects, suggesting that the mPFC may inhibit the POm neurons by activation of GABAergic ZI neurons. In conclusion, the mPFC may control the flow of somatosensory information through the thalamus by activation of S1 and ZI neurons.

Tactile response adaptation to whisker stimulation in the lemniscal somatosensory pathway of rats.

Response adaptation is associated with attenuation of neural responses as the result of different mechanisms. However, the main function of adaptation may be to enhance the flow of relevant information transmission in sensory pathways. To study tactile response adaptation in the somatosensory pathway, unit recordings were performed in the principal trigeminal nucleus, ventro postero-medial thalamic nucleus and barrel cortex by means of tungsten microelectrodes in urethane anesthetized rats. Tactile stimuli consisted in 20 ms duration whisker deflections at different frequencies (0.5-10 Hz). Presumably pyramidal cortical neurons showed response adaptation at frequencies >2 Hz while putative inhibitory cortical neurons did not show response adaptation at 0.5, 5 or 10 Hz. Inhibitory activity was increased by muscimol application into the cortex (8mM, 0.1 µl); in this condition cortical adaptation was not affected, suggesting that adaptation was not due to an increase of inhibitory mechanisms. Adaptation was also observed in subcortical structures although the response attenuation was lesser than in the barrel cortex. Adaptation remained in subcortical structures after reversible cortical inactivation by cooling the barrel cortex. Acetylcholine application (10 µM; 0.1 µl) into the barrel cortex reduced response adaptation through the activation of muscarinic receptors because the effect was blocked by intraperitoneal injection of atropine (1mg/kg), suggesting that adaptation may change according to the cortical Ach level. Results indicate that response adaptation increases along the somatosensory pathway probably to alter the sensitivity of neurons in order to encode sensory stimuli more efficiently and to enhance the detectability of rare stimuli.

Periarticular muscle stimulation controls anterior tibial laxity after experimental ACL section: an experimental study.

BACKGROUND AND PURPOSE: Besides current strategies to treat potentially disabling anterior cruciate ligament (ACL) injury, a new and innovative approach was designed based on electrical stimulation of the muscle to prevent unwanted displacement of the tibia relative to the femur. Our aim was to measure muscular strain and anterior tibial translation (ATT) in a controlled study using an animal model of ACL-deficient knee undergoing muscular electric stimulation. METHODS: Seventeen cat knees under tibial anterior traction of 24.5 N were studied before and after ACL transection. Muscular fiber length variation was obtained by ultrasonomicrometry and ATT by video recordings at the beginning, during, and at the end of the movement. Square pulses of 0.2 ms with 5 V were applied in trains of 500, 100, and 20 ms simultaneously to both the quadriceps and hamstrings before and immediately after traction. RESULTS: Electric stimulation of ACL-deficient knees normalized muscular strain to values of control knees. An increased resistance to muscular lengthening was observed in stimulated knees. Stimulation before traction maintained similar ATT than control knees during the subsequent traction. DISCUSSION: Electric muscular stimulation in the ACL-deficient knee provoked periarticular muscle contraction, controlling ATT when time-adjusted stimulus (before traction) was used. This suggested that artificially inducing the muscular response could help to control anterior knee laxity after ACL injury.

Corticofugal modulation of sensory information.

Sensory signals reach the cerebral cortex after having made synapses in different relay stations along the sensory pathway. The flow of sensory information in subcortical relay stations is controlled by the action of precise topographic connections from the neocortex. Several lines of research indicate that the massive corticifugal system improves ongoing subcortical sensory processing and reorganizes the receptive fields in visual, auditory and somatosensory systems. In all these sensory systems cortical neurons mediate both the highly focused positive feedback to subcortical neurons with overlapping receptive fields and a widespread inhibition to "non-matching neurons". This cortical feedback, which has been called "egocentric selection", can play a pivotal role in gating the sensory information that reaches the thalamus and cortex. Thus, corticofugal projections may contribute to selective attention since they enhance neuronal responses for attentionally relevant stimuli and by suppressing sensory responses of distractive stimuli. Also, corticofugal projections enhance oscillatory activity in order to synchronize neurons located in the same or in different relay stations in order to improve sensory processing. In conclusion, corticofugal pathways precisely control sensory transmission through out the central nervous system.