Plastic changes in the CNS in response to peripheral sensory nerve injury are a series of complex processes, ranging from local circuit remodeling to somatotopic reorganization. However, the link between circuit remodeling and somatotopic reorganization remains unclear. We have previously reported that transection of the primary whisker sensory nerve causes the abnormal rewiring of lemniscal fibers (sensory afferents) on a neuron in the mouse whisker sensory thalamus (V2 VPM). In the present study, using transgenic mice whose lemniscal fibers originate from the whisker sensory principle trigeminal nucleus (PrV2) are specifically labeled, we identified that the transection induced retraction of PrV2-originating lemniscal fibers and invasion of those not originating from PrV2 in the V2 VPM. This anatomical remodeling with somatotopic reorganization was highly correlated with the rewiring of lemniscal fibers. Origins of the non-PrV2-origin lemniscal fibers in the V2 VPM included the mandibular subregion of trigeminal nuclei and the dorsal column nuclei (DCNs), which normally represent body parts other than whiskers. The transection also resulted in ectopic receptive fields of V2 VPM neurons and extraterritorial pain behavior on the uninjured mandibular region of the face. The anatomical remodeling, emergence of ectopic receptive fields, and extraterritorial pain behavior all concomitantly developed within a week and lasted more than three months after the transection. Our findings, thus, indicate a strong linkage between these plastic changes after peripheral sensory nerve injury, which may provide a neural circuit basis underlying large-scale reorganization of somatotopic representation and abnormal ectopic sensations.

Psychological conditions affect pain responses in the human anterior cingulate cortex (ACC) according to brain imaging analysis. The rodent prefrontal cortex (PFC) including cingulate areas is also related to the affective dimension of pain. We previously reported PFC nociceptive responses inhibited by inputs from the amygdala, such as with dopamine (DA) D2 receptor (D2R) blockers, to show decreased effect on amygdala projections. In this study, we examined whether direct projections from the ventral tegmental area (VTA) to the PFC affect nociceptive responses in the PFC.

The dysbindin-1 gene (DTNBP1: dystrobrevin binding protein 1) is a promising schizophrenia susceptibility gene, known to localize almost exclusively to neurons in the brain, and participates in the regulation of neurotransmitter release, membrane-surface receptor expression, and synaptic plasticity. Sandy mice, with spontaneous Dtnbp1 deletion, display behavioral abnormalities relevant to symptoms of schizophrenia. However, it remains unknown if dysbindin-1 gain-of-function is beneficial or detrimental.

In the anterior lobe of the pituitary gland (AP), non-endocrine cells regulate hormone secretion by endocrine cells. However, the functions of non-endocrine cells in the AP during chronic pain are largely unclear. Here, we show that macrophages, but not folliculostellate (FS) cells, were selectively increased in the AP in the complete Freund's adjuvant (CFA)-induced chronic inflammatory pain model in rats. In addition, IL-1β expression was increased in the AP, and the IL-1β-immunopositive cells were identified as macrophages. On the other hand, increased macrophage density and IL-1β expression were not detected in a neuropathic pain model induced by partial sciatic nerve ligation (PSL). Furthermore, we found c-Fos expression specifically in the somatotrophs under the chronic inflammatory pain condition. Because IL-1β promotes growth hormone (GH) synthesis and release, our results suggest that AP macrophage contributes to GH release through IL-1βduring chronic inflammatory pain.　.

We previously demonstrated nociceptive discharges to be evoked by mechanical noxious stimulation in the prefrontal cortex (PFC). The nociceptive responses recorded in the PFC are conceivably involved in the affective rather than the sensory-discriminative dimension of pain. The PFC receives dense projection from the limbic system. Monosynaptic projections from the basolateral nucleus of the amygdala (BLA) to the PFC are known to produce long-lasting synaptic plasticity. We examined effects of high frequency stimulation (HFS) delivered to the BLA on nociceptive responses in the rat PFC.

Loss or gain of copy number of the gene encoding the transcription factor methyl-CpG-binding protein 2 (MeCP2) leads to neurodevelopmental disorders (Rett and MeCP2 duplication syndrome), indicating that precisely regulated MeCP2 expression during development is critical for mental health. Consistent with this idea, MeCP2 null mutants exhibit synaptic regression in the dorsal lateral geniculate nucleus (dLGN), the visual relay center in the thalamus, a phenotype resembling that of animals reared in the dark during the visual sensitive period. It remains unclear how MeCP2 expression is regulated during circuit formation and maturation, especially in excitatory and inhibitory populations of neurons. We found that, concomitant with the initiation of the dark-rearing sensitive period, MeCP2 protein levels were elevated in glutamatergic but not GABAergic neurons of the dLGN. Moreover, MeCP2 expression in glutamatergic populations was selectively reduced by dark-rearing. Therefore, we propose that visual experience-dependent MeCP2 induction in glutamatergic populations is essential for synaptic maturation within the dLGN.

We examined the effects of gamma knife (GK) irradiation on injured nerves using a rat partial sciatic nerve ligation (PSL) model. GK irradiation was performed at one week after ligation and nerve preparations were made three weeks after ligation. GK irradiation is known to induce immune responses such as glial cell activation in the central nervous system. Thus, we determined the effects of GK irradiation on macrophages using immunoblot and histochemical analyses. Expression of Iba-1 protein, a macrophage marker, was further increased in GK-treated injured nerves as compared with non-irradiated injured nerves. Immunohistochemical study of Iba-1 in GK-irradiated injured sciatic nerves demonstrated Iba-1 positive macrophage accumulation to be enhanced in areas distal to the ligation point. In the same area, myelin debris was also more efficiently removed by GK-irradiation. Myelin debris clearance by macrophages is thought to contribute to a permissive environment for axon growth. In the immunoblot study, GK irradiation significantly increased expressions of βIII-tubulin protein and myelin protein zero, which are markers of axon regeneration and re-myelination, respectively. Toluidine blue staining revealed the re-myelinated fiber diameter to be larger at proximal sites and that the re-myelinated fiber number was increased at distal sites in GK-irradiated injured nerves as compared with non-irradiated injured nerves. These results suggest that GK irradiation of injured nerves facilitates regeneration and re-myelination. In a behavior study, early alleviation of allodynia was observed with GK irradiation in PSL rats. When GK-induced alleviation of allodynia was initially detected, the expression of glial cell line-derived neurotrophic factor (GDNF), a potent analgesic factor, was significantly increased by GK irradiation. These results suggested that GK irradiation alleviates allodynia via increased GDNF. This study provides novel evidence that GK irradiation of injured peripheral nerves may have beneficial effects.

The metabotropic glutamate receptor subtype 1 (mGluR1) is a major subtype of group I mGluRs, which contributes to the development and plasticity of synapses in the brain. In the sensory thalamus, the thalamocortical neuron receives sensory afferents and massive feedback input from corticothalamic (CT) fibers. Notably, mGluR1 is more concentrated in CT synapses in the sensory thalamus. In the visual thalamus, mGluR1 maintains mature afferent synaptic connectivity. However, it is unknown whether mGluR1 contributes to strengthening of immature synapses or weakening of excess synapses during development and whether mGluR1 at CT synapses heterosynaptically regulates the development or refinement of afferent synapses. Here we investigated the effects of knocking out the gene encoding mGluR1 or pharmacologically blocking cortical activity on the development and maintenance of lemniscal synapses, i.e., the somatosensory afferent synapses, in the ventral posteromedial somatosensory thalamus. mGluR1-knockout (KO) mice exhibited delayed developmental strengthening as well as incomplete elimination and remodeling after maturation of lemniscal synapses. Similar to the phenotypes exhibited by mGluR1-KO mice, pharmacological blockade of somatosensory cortical activity from P12 or P21 for 1 week in wild-type mice perturbed elimination or maintenance of lemniscal synapses, respectively. The same manipulation in mGluR1-KO mice failed to induce additional abnormalities in lemniscal synaptic connectivity. These results suggest that activation of mGluR1, driven by CT input, regulates multiple stages of the development of lemniscal synapses, including strengthening, refinement, and maintenance in the somatosensory thalamus.

Abnormalities in GABAergic inhibitory circuits have been implicated in the aetiology of autism spectrum disorder (ASD). ASD is caused by genetic and environmental factors. Several genes have been associated with syndromic forms of ASD, including FOXG1. However, when and how dysregulation of FOXG1 can result in defects in inhibitory circuit development and ASD-like social impairments is unclear. Here, we show that increased or decreased FoxG1 expression in both excitatory and inhibitory neurons results in ASD-related circuit and social behavior deficits in our mouse models. We observe that the second postnatal week is the critical period when regulation of FoxG1 expression is required to prevent subsequent ASD-like social impairments. Transplantation of GABAergic precursor cells prior to this critical period and reduction in GABAergic tone via Gad2 mutation ameliorates and exacerbates circuit functionality and social behavioral defects, respectively. Our results provide mechanistic insight into the developmental timing of inhibitory circuit formation underlying ASD-like phenotypes in mouse models.