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Thalamocortical dysrhythmia is a key pathology of chronic neuropathic pain, but few studies have investigated thalamocortical networks in chronic low back pain (cLBP) given its non-specific etiology and complexity. Using fMRI, we propose an analytical pipeline to identify abnormal thalamocortical network dynamics in cLBP patients and validate the findings in two independent cohorts. We first identify two reoccurring dynamic connectivity states and their associations with chronic and temporary pain. Further analyses show that cLBP patients have abnormal connectivity between the ventral lateral/posterolateral nucleus (VL/VPL) and postcentral gyrus (PoCG) and between the dorsal/ventral medial nucleus and insula in the less frequent connectivity state, and temporary pain exacerbation alters connectivity between the VL/VPL and PoCG and the default mode network in the more frequent connectivity state. These results extend current findings on thalamocortical dysfunction and dysrhythmia in chronic pain and demonstrate that cLBP pathophysiology and clinical pain intensity are associated with distinct thalamocortical network dynamics. Thalamocortical dysrhythmia is a key pathology of chronic pain. Here, the authors propose an analytical pipeline to study dynamic fMRI brain networks and demonstrate that chronic low back pain pathophysiology and clinical pain intensity are associated with distinct thalamocortical network dynamics.

Depression, a prevalent psychiatric disorder of ambiguous etiology and high heterogeneity, has been recently linked to the primary visual cortex (V1). However, the precise circuits mediating the impact of V1 on depressive-like behaviors are poorly understood. Here, we demonstrate that the V1, specifically the lateral posterior nucleus of the thalamus (LP)-projecting V1 glutamatergic subpopulation (Glu V1→LP neurons), shows reduced activity after chronic restraint stress (CRS) in male mice, leading to depressive-like behaviors. Optogenetic or chemogenetic activation of these neurons ameliorated depressive-like behaviors in CRS-depressed mice, whereas reducing activity exacerbated these behaviors. This reduction in Glu V1→LP neurons activity was predominantly due to a decrease in the guanine nucleotide-binding protein subunit gamma-4 (Gγ4). Overexpression of Gγ4 in the Glu V1→LP neurons produced antidepressant-like effects, suggesting that Gγ4 is a crucial regulator of mood. Collectively, these results reveal a V1→LP circuit that modulates depressive-like behaviors, suggesting potential targets for therapeutic interventions. Depression has been recently linked to the visual cortex. Here, the authors identify a glutamatergic primary visual corticallateral posterior thalamic nucleus circuit and its key regulator, Gγ4, as modulators of depressive-like behaviors in male mice.

Psychophysics and brain imaging studies in deaf patients have revealed a functional crossmodal reorganization that affects the remaining sensory modalities. Similarly, the congenital deaf cat (CDC) shows supra-normal visual skills that are supported by specific auditory fields (DZ-dorsal zone and P-posterior auditory cortex) but not the primary auditory cortex (A1). To assess the functional reorganization observed in deafness we analyzed the connectivity pattern of the auditory cortex by means of injections of anatomical tracers in DZ and A1 in both congenital deaf and normally hearing cats. A quantitative analysis of the distribution of the projecting neurons revealed the presence of non-auditory inputs to both A1 and DZ of the CDC which were not observed in the hearing cats. Firstly, some visual (areas 19/20) and somatosensory (SIV) areas were projecting toward DZ of the CDC but not in the control. Secondly, A1 of the deaf cat received a weak projection from the visual lateral posterior nuclei (LP). Most of these abnormal projections to A1 and DZ represent only a small fraction of the normal inputs to these areas. In addition, most of the afferents to DZ and A1 appeared normal in terms of areal specificity and strength of projection, with preserved but smeared nucleotopic gradient of A1 in CDCs. In conclusion, while the abnormal projections revealed in the CDC can participate in the crossmodal compensatory mechanisms, the observation of a limited reorganization of the connectivity pattern of the CDC implies that functional reorganization in congenital deafness is further supported also by normal cortico-cortical connectivity.

Neuropathic pain involves complex cortical mechanisms, yet the role of the medial secondary visual cortex (V2M) remains poorly understood. We hypothesized that glutamatergic neurons in V2M (V2M Glu ) contribute to pain modulation and explored their functional involvement in both normal and neuropathic pain states. Here, we found that V2M Glu could be activated by peripheral stimulation under normal conditions. Optical inhibition or activation of unilateral V2M Glu respectively decreased or increased bilateral nociceptive sensitivity, with activation also inducing aversive emotions. Tracing experiments revealed that V2M Glu sends dense synaptic projections to the lateral posterior thalamic nucleus (LP) and lateral dorsal thalamic nucleus (LD). Notably, only optical manipulation of V2M Glu terminals in LP, rather than LD, affected bilateral pain perception. Following partial sciatic nerve ligation (PSL), V2M Glu exhibited hyperactivity, including increased spontaneous spike frequency and heightened responses to stimulation. Inhibiting V2M Glu alleviated PSL-induced mechanical allodynia, thermal hyperalgesia, and negative affective states related to pain. Inhibition of V2M Glu terminals in LP mitigated neuropathic pain. Here, we identified V2M Glu and its circuits to LP as part of the endogenous pain modulatory network, hyperactive after peripheral nerve injury and contributing to neuropathic pain. Our findings support targeting V2M Glu and related circuits as potential therapeutic strategies for neuropathic pain. Optogenetics reveals the crucial role of glutamatergic neurons in the medial secondary visual cortex (V2M) in modulating nociceptive sensitivity and negative emotions under both physiological and neuropathic pain conditions.

Rapidly approaching objects indicating threats can induce defensive response through activating a subcortical pathway comprising superior colliculus (SC), lateral posterior nucleus (LP), and basolateral amygdala (BLA). Abnormal defensive response has been reported in autism, and impaired synaptic connections could be the underlying mechanism. Whether the SC-LP-BLA pathway processes looming stimuli abnormally in autism is not clear. Here, we found that looming-evoked defensive response is impaired in a subgroup of the valproic acid (VPA) mouse model of autism. By combining the conventional neurotracer and transneuronal rabies virus tracing techniques, we demonstrated that synaptic connections in the SC-LP-BLA pathway were abnormal in VPA mice whose looming-evoked defensive responses were absent. Importantly, we further translated the finding to children with autism and observed that they did not present looming-evoked defensive response. Furthermore, the findings of the DTI with the probabilistic tractography showed that the structural connections of SC-pulvinar-amygdala in autism children were weak. The pulvinar is parallel to the LP in a mouse. Because looming-evoked defensive response is innate in humans and emerges much earlier than do social and language functions, the absence of defensive response could be an earlier sign of autism in children.

Spontaneous action potential bursts associated with low threshold calcium spikes (LTS) occur in multiple human lateral thalamic nuclei, each with different physiologic characteristics. We now test the hypothesis that different patterns of spontaneous LTS bursting occur in these nuclei during awake surgery in patients with essential tremor and the arm at rest. This protocol was chosen to minimize the effect of the patient's disease upon thalamic activity which is a potential confound in a surgical study of this type. Neuronal activity was studied in the human thalamic nuclei receiving somatic sensory input (Vc, ventral caudal), input from the deep cerebellar nuclei (Vim, ventral intermediate), or input from the pallidum (Vo, ventral oral). In each nucleus the burst rates were significantly greater than zero. Burst rates were higher in Vc than in Vim, while firing rates were lower. These findings suggest that neurons in Vc are hyperpolarized and have more frequent inhibitory events. Pre-burst inter-spike intervals (ISIs) were significantly longer in Vc, but were significantly shorter when corrected for the average ISIs between bursts (burst rate/inverse of the primary event rate). These results suggest that inhibitory events in Vc are of lower magnitude relative to a hyperpolarized resting membrane potential. Studies in many species demonstrate that input from the pallidum to the thalamus is inhibitory, suggesting that input to Vo is predominantly inhibitory. However, neurons in Vo have neither slower firing rates nor more frequent LTS bursts. Previous studies have found that spontaneous LTS is similar between classes of neurons within Vc, as defined by their response to thermal and painful stimuli. The differences in spontaneous LTS between human nuclei but not between functional classes within a nucleus may be a basic organizing principle of thalamic inhibitory circuitry.

Sleep is integral to cardiovascular health 1 , 2 . Yet, the circuits that connect cardiovascular pathology and sleep are incompletely understood. It remains unclear whether cardiac injury influences sleep and whether sleep-mediated neural outputs contribute to heart healing and inflammation. Here we report that in humans and mice, monocytes are actively recruited to the brain after myocardial infarction (MI) to augment sleep, which suppresses sympathetic outflow to the heart, limiting inflammation and promoting healing. After MI, microglia rapidly recruit circulating monocytes to the brain’s thalamic lateral posterior nucleus (LPN) via the choroid plexus, where they are reprogrammed to generate tumour necrosis factor (TNF). In the thalamic LPN, monocytic TNF engages Tnfrsf1a -expressing glutamatergic neurons to increase slow wave sleep pressure and abundance. Disrupting sleep after MI worsens cardiac function, decreases heart rate variability and causes spontaneous ventricular tachycardia. After MI, disrupting or curtailing sleep by manipulating glutamatergic TNF signalling in the thalamic LPN increases cardiac sympathetic input which signals through the β2-adrenergic receptor of macrophages to promote a chemotactic signature that increases monocyte influx. Poor sleep in the weeks following acute coronary syndrome increases susceptibility to secondary cardiovascular events and reduces the heart’s functional recovery. In parallel, insufficient sleep in humans reprogrammes β2-adrenergic receptor-expressing monocytes towards a chemotactic phenotype, enhancing their migratory capacity. Collectively, our data uncover cardiogenic regulation of sleep after heart injury, which restricts cardiac sympathetic input, limiting inflammation and damage. Studies in humans and mice show that myocardial infarction recruits monocytes to the brain’s thalamus, promoting sleep, which in turn restricts cardiac inflammation and sympathetic signalling and assists healing.

Mechanisms underlying remifentanil- (RF-) induced hyperalgesia, a phenomenon that is generally named as opioid-induced hyperalgesia (OIH), still remain elusive. The ventral posterior lateral nucleus (VPL) of the thalamus, a key relay station for the transmission of nociceptive information to the cerebral cortex, is activated by RF infusion. Electroacupuncture (EA) is an effective method for the treatment of pain. This study aimed to explore the role of VPL in the development of OIH and the effect of EA treatment on OIH in rats. RF was administered to rats via the tail vein for OIH induction. Paw withdrawal threshold (PWT) in response to mechanical stimuli and paw withdrawal latency (PWL) to thermal stimulation were tested in rats for the assessment of mechanical allodynia and thermal hyperalgesia, respectively. Spontaneous neuronal activity and local field potential (LFP) in VPL were recorded in freely moving rats using the in vivo multichannel recording technique. EA at 2 Hz frequency (pulse width 0.6 ms, 1–3 mA) was applied to the bilateral acupoints “Zusanli” (ST.36) and “Sanyinjiao” (SP.6) in rats. The results showed that both the PWT and PWL were significantly decreased after RF infusion to rats. Meanwhile, both the spontaneous neuronal firing rate and the theta band oscillation in VPL LFP were increased on day 3 post-RF infusion, indicating that the VPL may promote the development of RF-induced hyperalgesia by regulating the pain-related cortical activity. Moreover, 2 Hz-EA reversed the RF-induced decrease both in PWT and PWL of rats and also abrogated the RF-induced augmentation of the spontaneous neuronal activity and the power spectral density (PSD) of the theta band oscillation in VPL LFP. These results suggested that 2 Hz-EA attenuates the remifentanil-induced hyperalgesia via reducing the excitability of VPL neurons and the low-frequency (theta band) oscillation in VPL LFP.

Background Mental disorders frequently co‐occur with pain, yet pain mechanisms in non‐peripheral etiologies (e.g., chronic psychological stress) remain underexplored. The ventral anterior–lateral thalamic complex (VAL) is implicated in emotional processing, but its role in chronic stress‐induced pain hypersensitivity is unclear. Electroacupuncture (EA) is clinically used for pain management, but its efficacy and mechanisms in chronic stress‐driven pain hypersensitivity require validation. Methods A chronic restraint stress (CRS) model was established in male mice. Behavioral assessments were performed to quantify mechanical sensitivity (hindpaws and abdomen using von Frey filaments), thermal sensitivity (hot plate test), and spontaneous pain‐like behaviors. Bidirectional chemogenetic approaches targeted VAL CaMKIIα‐positive neurons. EA was applied at Zusanli (ST36) and Sanyinjiao (SP6) acupoints. Results CRS stably induced pain hypersensitivity phenotypes, including mechanical allodynia (hindpaws/abdomen), thermal hyperalgesia, and spontaneous pain‐like behaviors. Chemogenetic inhibition of VAL CaMKIIα‐positive neurons reversed these CRS‐induced hypersensitivity responses. Conversely, activating these neurons in naive mice recapitulated the full spectrum of hyperalgesia phenotypes. EA alleviated CRS‐induced hindpaw mechanical/thermal hyperalgesia, abdominal allodynia, and spontaneous pain. EA's effects on hindpaw mechanical/thermal hyperalgesia were mediated by suppression of VAL CaMKIIα‐positive neurons. In contrast, its amelioration of abdominal allodynia and spontaneous pain persisted despite chemogenetic activation of VAL CaMKIIα‐positive neurons, indicating possible distinct pathways. Conclusion This study reveals the pivotal role of thalamic VAL CaMKIIα‐positive neurons in chronic stress‐associated pain hypersensitivity and elucidates EA's analgesic mechanisms, providing novel therapeutic strategies for emotion–pain comorbidity. Chronic restraint stress (CRS) necessarily and sufficiently induces hyperalgesia by activating ventral anterior–lateral complex of the thalamus (VAL) CaMKIIα‐positive neurons. Electroacupuncture alleviates CRS‐induced paw mechanical allodynia and thermal hyperalgesia by suppressing these VAL neurons.

Objective: Reduction of melanocortin signaling in the brain results in obesity. However, where in the brain reduced melanocortin signaling mediates this effect is poorly understood. Design: We determined the effects of long-term inhibition of melanocortin receptor activity in specific brain regions of the rat brain. Melanocortin signaling was inhibited by injection of a recombinant adeno-associated viral (rAAV) vector that overexpressed Agouti-related peptide (AgRP) into the paraventricular nucleus (PVN), the ventromedial hypothalamus (VMH), the lateral hypothalamus (LH) or the accumbens shell (Acc). Results: Overexpression of AgRP in the rat PVN, VMH or LH increased bodyweight, the percentage of white adipose tissue, plasma leptin and insulin concentrations and food intake. Food intake was mainly increased because of an increase in meal size in the light and dark phases, after overexpression of AgRP in the PVN, LH or VMH. Overexpression of AgRP in the PVN or VMH reduced average body core temperature in the dark on day 40 post injection, whereas AgRP overexpression in the LH did not affect temperature. In addition, overexpression of AgRP in the PVN, LH or VMH did not significantly alter mRNA expression of AgRP, neuropeptide Y (NPY), pro-opiomelanocortin (POMC) or suppressor of cytokine signaling 3 (SOCS3) in the arcuate. Overexpression of AgRP in the Acc did not have any effect on the measured parameters. Conclusions: Reduction of melanocortin signaling in several hypothalamic regions increased meal size. However, there were brain area-specific effects on other parameters such as core temperature and plasma leptin concentrations. In a previous study, where NPY was overexpressed with an rAAV vector in the PVN and LH, meal frequency and meal size were increased respectively, whereas locomotor activity was reduced by NPY overexpression at both nuclei. Taken together, AgRP and NPY have complementary roles in energy balance.