The prefrontal-hippocampal dysfunction that underlies cognitive deficits in mental disorders emerges during early development. The lateral entorhinal cortex (LEC) is tightly interconnected with both ...prefrontal cortex (PFC) and hippocampus (HP), yet its contribution to the early dysfunction is fully unknown. Here we show that mice that mimic the dual genetic (G) -environmental (E) etiology (GE mice) of psychiatric risk have poor LEC-dependent recognition memory at pre-juvenile age and abnormal communication within LEC-HP-PFC networks throughout development. These functional and behavioral deficits relate to sparser projections from LEC to CA1 and decreased efficiency of axonal terminals to activate the hippocampal circuits in neonatal GE mice. In contrast, the direct entorhinal drive to PFC is not affected, yet the PFC is indirectly compromised, as target of the under-activated HP. Thus, the entorhinal-hippocampal circuit is already impaired from neonatal age on in GE mice.
Abstract The potential brain mechanism underlying resilience to socially transferred allodynia remains unknown. Here, we utilize a well-established socially transferred allodynia paradigm to ...segregate male mice into pain-susceptible and pain-resilient subgroups. Brain screening results show that ventral tegmental area glutamatergic neurons are selectively activated in pain-resilient mice as compared to control and pain-susceptible mice. Chemogenetic manipulations demonstrate that activation and inhibition of ventral tegmental area glutamatergic neurons bi-directionally regulate resilience to socially transferred allodynia. Moreover, ventral tegmental area glutamatergic neurons that project specifically to the nucleus accumbens shell and lateral habenula regulate the development and maintenance of the pain-resilient phenotype, respectively. Together, we establish an approach to explore individual variations in pain response and identify ventral tegmental area glutamatergic neurons and related downstream circuits as critical targets for resilience to socially transferred allodynia and the development of conceptually innovative analgesics.
The paucity of medications with novel mechanisms for pain treatment combined with the severe adverse effects of opioid analgesics has led to an imperative pursuit of non-opioid analgesia and a better ...understanding of pain mechanisms. Here, we identify the putative glutamatergic inputs from the paraventricular thalamic nucleus to the nucleus accumbens (PVTGlut→NAc) as a novel neural circuit for pain sensation and non-opioid analgesia. Our in vivo fiber photometry and in vitro electrophysiology experiments found that PVTGlut→NAc neuronal activity increased in response to acute thermal/mechanical stimuli and persistent inflammatory pain. Direct optogenetic activation of these neurons in the PVT or their terminals in the NAc induced pain-like behaviors. Conversely, inhibition of PVTGlut→NAc neurons or their NAc terminals exhibited a potent analgesic effect in both naïve and pathological pain mice, which could not be prevented by pretreatment of naloxone, an opioid receptor antagonist. Anterograde trans-synaptic optogenetic experiments consistently demonstrated that the PVTGlut→NAc circuit bi-directionally modulates pain behaviors. Furthermore, circuit-specific molecular profiling and pharmacological studies revealed dopamine receptor 3 as a candidate target for pain modulation and non-opioid analgesic development. Taken together, these findings provide a previously unknown neural circuit for pain sensation and non-opioid analgesia and a valuable molecular target for developing future safer medication.
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●PVTGlut→NAc circuit is activated by noxious stimuli.●PVTGlut→NAc circuit bi-directionally regulates pain behaviors.●PVTGlut→NAc circuit mediates the development of CFA persistent inflammatory pain.●Inhibition of PVTGlut→NAc circuit has a non-opioid analgesic effect.●Dopamine receptor 3 is a candidate target for non-opioid analgesic development.
In reeler mutant mice, which are deficient in reelin (Reln), the lamination of the cerebral cortex is disrupted. Reelin signaling induces phosphorylation of LIM kinase 1, which phosphorylates the ...actin-depolymerizing protein cofilin in migrating neurons. Conditional cofilin mutants show neuronal migration defects. Thus, both reelin and cofilin are indispensable during cortical development. To analyze the effects of cofilin phosphorylation on neuronal migration we used in utero electroporation to transfect E14.5 wild-type cortical neurons with pCAG-EGFP plasmids encoding either a nonphosphorylatable form of cofilin 1 (cofilin(S3A)), a pseudophosphorylated form (cofilin(S3E)) or wild-type cofilin 1 (cofilin(WT)). Wild-type controls and reeler neurons were transfected with pCAG-EGFP. Real-time microscopy and histological analyses revealed that overexpression of cofilin(WT) and both phosphomutants induced migration defects and morphological abnormalities of cortical neurons. Of note, reeler neurons and cofilin(S3A)- and cofilin(S3E)-transfected neurons showed aberrant backward migration towards the ventricular zone. Overexpression of cofilin(S3E), the pseudophosphorylated form, partially rescued the migration defect of reeler neurons, as did overexpression of Limk1. Collectively, the results indicate that reelin and cofilin cooperate in controlling cytoskeletal dynamics during neuronal migration.
The long-range coupling within prefrontal-hippocampal networks that account for cognitive performance emerges early in life. The discontinuous hippocampal theta bursts have been proposed to drive the ...generation of neonatal prefrontal oscillations, yet the cellular substrate of these early interactions is still unresolved. Here, we selectively target optogenetic manipulation of glutamatergic projection neurons in the CA1 area of either dorsal or intermediate/ventral hippocampus at neonatal age to elucidate their contribution to the emergence of prefrontal oscillatory entrainment. We show that despite stronger theta and ripples power in dorsal hippocampus, the prefrontal cortex is mainly coupled with intermediate/ventral hippocampus by phase-locking of neuronal firing via dense direct axonal projections. Theta band-confined activation by light of pyramidal neurons in intermediate/ventral but not dorsal CA1 that were transfected by
electroporation with high-efficiency channelrhodopsin boosts prefrontal oscillations. Our data causally elucidate the cellular origin of the long-range coupling in the developing brain.
Abstract During brain development, the radial glial cell acts as a scaffold to support radial migration of postmitotic neurons. However, the morphological changes of radial glial cells during embryo ...development are poorly understood. We used in utero electroporation and immunohistochemistry to study the dynamics of radial glial cells accompanied by cortical development in mice from embryonic day 14 to postnatal day 0. We found that different segments of radial glial cells changed by the growth of different layers of cortex, such as marginal zone, cortical plate, intermediate zone and ventricular zone. Moreover, the length, angle and number of branches of the radial glial cell changed significantly at the late stage of neurogenesis. All these changes were consistent with the distinct phases of locomotion. Thus, we speculated that morphological changes of the radial glial cell were associated with the neuronal migration and dendritic development.
•Swainsonine inhibits the proliferation of neuro-2a cells and causes cell death.•Swainsonine damages adult neurogenesis in mouse.•Swainsonine impairs mouse learning and memory behavior.
Swainsonine ...(SW) is an indolizidine triol plant alkaloid isolated from the species Astragalus, colloquially termed locoweed. Ingestion induces severe neurological symptoms of livestock and wildlife, including ataxia, trembling, exaggerated fright reactions. Toxicity to the central and peripheral nervous system is caused by inhibition of lysosomal a-mannosidase (AMA) and accumulation of intracellular oligosaccharide. However, the effects of SW on adult neurogenesis and cognition have remained unclear. Therefore, the present study was conducted to examine the effects of SW on adult neurogenesis and learning as well as memory performance in adult mice. SW (10μg/mL in drinking water) was administered orally to mice for 4 weeks. Our results showed that SW reduced proliferation and survival of neural progenitor cells (NPCs) in culture, and in the hippocampus of adult mice. In addition, exposure to SW led to down-regulation of doublecortin (DCX) and synaptophysin (SYP) in the hippocampus. However, caspase 3 and glial fibrillary acidic protein (GFAP) levels were significantly increased in SW-treated mice. Finally, SW-treated mice exhibited deficits in hippocampus-dependent spatial learning and memory. Our findings suggest that SW affects adult neurogenesis and cognitive function.
The adult neocortex is a six-layered structure, consisting of nearly continuous layers of neurons that are generated in a temporally strictly coordinated order. During development, cortical neurons ...originating from the ventricular zone migrate toward the Reelin-containing marginal zone in an inside-out arrangement. Focal adhesion kinase (FAK), one tyrosine kinase localizing to focal adhesions, has been shown to be phosphorylated at tyrosine 925 (Y925) by Src, an important downstream molecule of Reelin signaling. Up to date, the precise molecular mechanisms of FAK and its phosphorylation at Y925 during neuronal migration are still unclear. Combining
in utero
electroporation with immunohistochemistry and live imaging, we examined the function of FAK in regulating neuronal migration. We show that phosphorylated FAK is colocalized with Reelin positive Cajal-Retzius cells in the developing neocortex and hippocampus. Phosphorylation of FAK at Y925 is significantly reduced in
reeler
mice. Overexpression and dephosphorylation of FAK impair locomotion and translocation, resulting in migration inhibition and dislocation of both late-born and early-born neurons. These migration defects are highly correlated to the function of FAK in regulating cofilin phosphorylation and N-Cadherin expression, both are involved in Reelin signaling pathway. Thus, fine-tuned phosphorylation of focal adhesion kinase at Y925 is crucial for both glia-dependent and independent neuronal migration.
Neurons in the developing brain form the cortical plate (CP) in an inside-out manner, in which the late-born neurons are located more superficially than the early-born neurons. Fyn, a member of the ...Src family kinases, plays an important role in neuronal migration by binding to many substrates. However, the role of the Src-homology 2 (SH2) domain in function of Fyn in neuronal migration remains poorly understood. Here, we demonstrate that the SH2 domain is essential for the action of Fyn in neuronal migration and cortical lamination. A point mutation in the Fyn SH2 domain (FynR176A) impaired neuronal migration and their final location in the cerebral cortex, by inducing neuronal aggregation and branching. Thus, we provide the first evidence of the Fyn SH2 domain contributing to neuronal migration and neuronal morphogenesis.
Abstract
Disrupted-in-schizophrenia 1 (DISC1) gene represents an intracellular hub of developmental processes. When combined with early environmental stressors, such as maternal immune activation, ...but not in the absence of thereof, whole-brain DISC1 knock-down leads to memory and executive deficits as result of impaired prefrontal–hippocampal communication throughout development. While synaptic dysfunction in neonatal prefrontal cortex (PFC) has been recently identified as one source of abnormal long-range coupling, the contribution of hippocampus (HP) is still unknown. Here, we aim to fill this knowledge gap by combining in vivo electrophysiology and optogenetics with morphological and behavioral assessment of immune-challenged mice with DISC1 knock-down either in the whole brain (GE) or restricted to pyramidal neurons in hippocampal CA1 area (GHPE). We found abnormal network activity, sharp-waves, and neuronal firing in CA1 that complement the deficits in upper layer of PFC. Moreover, optogenetic activating CA1 pyramidal neurons fails to activate the prefrontal local circuits. These deficits that persist till prejuvenile age relate to dendrite sparsification and loss of spines of CA1 pyramidal neurons. As a long-term consequence, DISC1 knock-down in HP leads to poorer recognition memory at prejuvenile age. Thus, DISC1-controlled developmental processes in HP in immune-challenged mice are critical for circuit function and cognitive behavior.
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