The Journal of neuroscience : the official journal of the Society for Neuroscience
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For many years, neurobiological theories have emphasized the importance of neuronal oscillations in the emergence of brain function. At the same time, clinical studies have shown that disturbances or irregularities in brain rhythms may relate to various common neurological conditions, including migraine. Increasing evidence suggests that the CNS plays a fundamental role in the predisposition to develop different forms of headache. Here, we present human imaging data that strongly support the presence of abnormal low-frequency oscillations (LFOs) in thalamocortical networks of patients in the interictal phase of migraine. Our results show that the main source of arrhythmic activity was localized to the higher-order thalamic relays of the medial dorsal nucleus. In addition, spontaneous LFOs in the thalamus were selectively associated with the headache attack frequency, meaning that the varying amplitude of dysrhythmia could predispose patients to recurrent attacks. Rhythmic cortical feedback to the thalamus is a major factor in the amplification of thalamocortical oscillations, making it a strong candidate for influencing neuronal excitability. We further speculate that the intrinsic dynamics of thalamocortical network oscillations are crucial for early sensory processing and therefore could underlie important pathophysiological processes involved in multisensory integration. ⋯ In many cases, migraine attacks are thought to begin centrally. A major obstacle to studying intrinsic brain activity has been the identification of the precise anatomical structures and functional networks that are involved in migraine. Here, we present imaging data that strongly support the presence of abnormal low-frequency oscillations in thalamocortical networks of patients in the interictal phase of migraine. This arrhythmic activity was localized to the higher-order thalamic relays of the medial dorsal nucleus and was selectively associated with headache attack frequency. Rhythmic cortical feedback to the thalamus is a major factor in the amplification of thalamocortical oscillations, making it a strong candidate for influencing neuronal excitability and higher-level processes involved in multisensory integration.
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Behavioral states are commonly considered global phenomena with homogeneous neural determinants. However, recent studies indicate that behavioral states modulate spiking activity with neuron-level specificity as a function of brain area, neuronal subtype, and preceding history. Although functional connectivity also strongly depends on behavioral state at a mesoscopic level and is globally weaker in non-REM (NREM) sleep and anesthesia than wakefulness, it is unknown how neuronal communication is modulated at the cellular level. We hypothesize that, as for neuronal activity, the influence of behavioral states on neuronal coupling strongly depends on type, location, and preceding history of involved neurons. Here, we applied nonlinear, information-theoretical measures of functional connectivity to ensemble recordings with single-cell resolution to quantify neuronal communication in the neocortex and hippocampus of rats during wakefulness and sleep. Although functional connectivity (measured in terms of coordination between firing rate fluctuations) was globally stronger in wakefulness than in NREM sleep (with distinct traits for cortical and hippocampal areas), the drop observed during NREM sleep was mainly determined by a loss of inter-areal connectivity between excitatory neurons. Conversely, local (intra-area) connectivity and long-range (inter-areal) coupling between interneurons were preserved during NREM sleep. Furthermore, neuronal networks that were either modulated or not by a behavioral task remained segregated during quiet wakefulness and NREM sleep. These results show that the drop in functional connectivity during wake-sleep transitions globally holds true at the cellular level, but confine this change mainly to long-range coupling between excitatory neurons. ⋯ Studies performed at a mesoscopic level of analysis have shown that communication between cortical areas is disrupted in non-REM sleep and anesthesia. However, the neuronal determinants of this phenomenon are not known. Here, we applied nonlinear, information-theoretical measures of functional coupling to multi-area tetrode recordings from freely moving rats to investigate whether and how brain state modulates coordination between individual neurons. We found that the previously observed drop in functional connectivity during non-REM (NREM) sleep can be explained by a decrease in coupling between excitatory neurons located in distinct brain areas. Conversely, intra-area communication and coupling between interneurons are preserved. Our results provide significant new insights into the neuron-level mechanisms responsible for the loss of consciousness occurring in NREM sleep.
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The precise neural mechanisms underlying transitions between consciousness and anesthetic-induced unconsciousness remain unclear. Here, we studied intracortical neuronal dynamics leading to propofol-induced unconsciousness by recording single-neuron activity and local field potentials directly in the functionally interconnecting somatosensory (S1) and frontal ventral premotor (PMv) network during a gradual behavioral transition from full alertness to loss of consciousness (LOC) and on through a deeper anesthetic level. Macaque monkeys were trained for a behavioral task designed to determine the trial-by-trial alertness and neuronal response to tactile and auditory stimulation. We show that disruption of coherent beta oscillations between S1 and PMv preceded, but did not coincide with, the LOC. LOC appeared to correspond to pronounced but brief gamma-/high-beta-band oscillations (lasting ∼3 min) in PMv, followed by a gamma peak in S1. We also demonstrate that the slow oscillations appeared after LOC in S1 and then in PMv after a delay, together suggesting that neuronal dynamics are very different across S1 versus PMv during LOC. Finally, neurons in both S1 and PMv transition from responding to bimodal (tactile and auditory) stimulation before LOC to only tactile modality during unconsciousness, consistent with an inhibition of multisensory integration in this network. Our results show that propofol-induced LOC is accompanied by spatiotemporally distinct oscillatory neuronal dynamics across the somatosensory and premotor network and suggest that a transitional state from wakefulness to unconsciousness is not a continuous process, but rather a series of discrete neural changes. ⋯ How information is processed by the brain during awake and anesthetized states and, crucially, during the transition is not clearly understood. We demonstrate that neuronal dynamics are very different within an interconnecting cortical network (primary somatosensory and frontal premotor area) during the loss of consciousness (LOC) induced by propofol in nonhuman primates. Coherent beta oscillations between these regions are disrupted before LOC. Pronounced but brief gamma-band oscillations appear to correspond to LOC. In addition, neurons in both of these cortices transition from responding to both tactile and auditory stimulation before LOC to only tactile modality during unconsciousness. We demonstrate that propofol-induced LOC is accompanied by spatiotemporally distinctive neuronal dynamics in this network with concurrent changes in multisensory processing.
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Anatomical studies have identified brainstem neurons that project bilaterally to left and right oromotor pools, which could potentially mediate bilateral muscle coordination. We use retrograde lentiviruses combined with a split-intein-mediated split-Cre-recombinase system in mice to isolate, characterize, and manipulate a population of neurons projecting to both the left and right jaw-closing trigeminal motoneurons. We find that these bilaterally projecting premotor neurons (BPNs) reside primarily in the supratrigeminal nucleus (SupV) and the parvicellular and intermediate reticular regions dorsal to the facial motor nucleus. These BPNs also project to multiple midbrain and brainstem targets implicated in orofacial sensorimotor control, and consist of a mix of glutamatergic, GABAergic, and glycinergic neurons, which can drive both excitatory and inhibitory inputs to trigeminal motoneurons when optogenetically activated in slice. Silencing BPNs with tetanus toxin light chain (TeNT) increases bilateral masseter activation during chewing, an effect driven by the expression of TeNT in SupV BPNs. Acute unilateral optogenetic inhibition of SupV BPNs identifies a group of tonically active neurons that function to lower masseter muscle tone, whereas unilateral optogenetic activation of SupV BPNs is sufficient to induce bilateral masseter activation both during resting state and during chewing. These results provide evidence for SupV BPNs in tonically modulating jaw-closing muscle tone and in mediating bilateral jaw closing. ⋯ We developed a method that combines retrograde lentiviruses with the split-intein-split-Cre system in mice to isolate, characterize, and manipulate neurons that project to both left and right jaw-closing motoneurons. We show that these bilaterally projecting premotor neurons (BPNs) reside primarily in the supratrigeminal nucleus and the rostral parvicellular and intermediate reticular nuclei. BPNs consist of both excitatory and inhibitory populations, and also project to multiple brainstem nuclei implicated in orofacial sensorimotor control. Manipulation of the supratrigeminal BPNs during natural jaw-closing behavior reveals a dual role for these neurons in eliciting phasic muscle activation and in maintaining basal muscle tone. The retrograde lentivirus carrying the split-intein-split-Cre system can be applied to study any neurons with bifurcating axons innervating two brain regions.
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Acute brain ischemia induces a local neuroinflammatory reaction and alters peripheral immune homeostasis at the same time. Recent evidence has suggested a key role of the gut microbiota in autoimmune diseases by modulating immune homeostasis. Therefore, we investigated the mechanistic link among acute brain ischemia, microbiota alterations, and the immune response after brain injury. Using two distinct models of acute middle cerebral artery occlusion, we show by next-generation sequencing that large stroke lesions cause gut microbiota dysbiosis, which in turn affects stroke outcome via immune-mediated mechanisms. Reduced species diversity and bacterial overgrowth of bacteroidetes were identified as hallmarks of poststroke dysbiosis, which was associated with intestinal barrier dysfunction and reduced intestinal motility as determined by in vivo intestinal bolus tracking. Recolonizing germ-free mice with dysbiotic poststroke microbiota exacerbates lesion volume and functional deficits after experimental stroke compared with the recolonization with a normal control microbiota. In addition, recolonization of mice with a dysbiotic microbiome induces a proinflammatory T-cell polarization in the intestinal immune compartment and in the ischemic brain. Using in vivo cell-tracking studies, we demonstrate the migration of intestinal lymphocytes to the ischemic brain. Therapeutic transplantation of fecal microbiota normalizes brain lesion-induced dysbiosis and improves stroke outcome. These results support a novel mechanism in which the gut microbiome is a target of stroke-induced systemic alterations and an effector with substantial impact on stroke outcome. ⋯ We have identified a bidirectional communication along the brain-gut microbiota-immune axis and show that the gut microbiota is a central regulator of immune homeostasis. Acute brain lesions induced dysbiosis of the microbiome and, in turn, changes in the gut microbiota affected neuroinflammatory and functional outcome after brain injury. The microbiota impact on immunity and stroke outcome was transmissible by microbiota transplantation. Our findings support an emerging concept in which the gut microbiota is a key regulator in priming the neuroinflammatory response to brain injury. These findings highlight the key role of microbiota as a potential therapeutic target to protect brain function after injury.