A Central Amygdala-Ventrolateral Periaqueductal Gray Matter Pathway for Pain in a Mouse Model of Depression-like Behavior.

BACKGROUND: The mechanisms underlying depression-associated pain remain poorly understood. Using a mouse model of depression, the authors hypothesized that the central amygdala-periaqueductal gray circuitry is involved in pathologic nociception associated with depressive states. METHODS: The authors used chronic restraint stress to create a mouse model of nociception with depressive-like behaviors. They then used retrograde tracing strategies to dissect the pathway from the central nucleus of the amygdala to the ventrolateral periaqueductal gray. The authors performed optogenetic and chemogenetic experiments to manipulate the activity of this pathway to explore its roles for nociception. RESULTS: The authors found that γ-aminobutyric acid-mediated (GABAergic) neurons from the central amygdala project onto GABAergic neurons of the ventrolateral periaqueductal gray, which, in turn, locally innervate their adjacent glutamatergic neurons. After chronic restraint stress, male mice displayed reliable nociception (control, mean ± SD: 0.34 ± 0.11 g, n = 7 mice; chronic restraint stress, 0.18 ± 0.11 g, n = 9 mice, P = 0.011). Comparable nociception phenotypes were observed in female mice. After chronic restraint stress, increased circuit activity was generated by disinhibition of glutamatergic neurons of the ventrolateral periaqueductal gray by local GABAergic interneurons via receiving enhanced central amygdala GABAergic inputs. Inhibition of this circuit increased nociception in chronic restraint stress mice (median [25th, 75th percentiles]: 0.16 [0.16, 0.16] g to 0.07 [0.04, 0.16] g, n = 7 mice per group, P < 0.001). In contrast, activation of this pathway reduced nociception (mean ± SD: 0.16 ± 0.08 g to 0.34 ± 0.13 g, n = 7 mice per group, P < 0.001). CONCLUSIONS: These findings indicate that the central amygdala-ventrolateral periaqueductal gray pathway may mediate some aspects of pain symptoms under depression conditions.

The long noncoding RNA Synage regulates synapse stability and neuronal function in the cerebellum.

The brain is known to express many long noncoding RNAs (lncRNAs); however, whether and how these lncRNAs function in modulating synaptic stability remains unclear. Here, we report a cerebellum highly expressed lncRNA, Synage, regulating synaptic stability via at least two mechanisms. One is through the function of Synage as a sponge for the microRNA miR-325-3p, to regulate expression of the known cerebellar synapse organizer Cbln1. The other function is to serve as a scaffold for organizing the assembly of the LRP1-HSP90AA1-PSD-95 complex in PF-PC synapses. Although somewhat divergent in its mature mRNA sequence, the locus encoding Synage is positioned adjacent to the Cbln1 loci in mouse, rhesus macaque, and human, and Synage is highly expressed in the cerebella of all three species. Synage deletion causes a full-spectrum cerebellar ablation phenotype that proceeds from cerebellar atrophy, through neuron loss, on to synapse density reduction, synaptic vesicle loss, and finally to a reduction in synaptic activity during cerebellar development; these deficits are accompanied by motor dysfunction in adult mice, which can be rescued by AAV-mediated Synage overexpression from birth. Thus, our study demonstrates roles for the lncRNA Synage in regulating synaptic stability and function during cerebellar development.

A somatosensory cortex input to the caudal dorsolateral striatum controls comorbid anxiety in persistent pain.

Chronic pain and anxiety symptoms are frequently encountered clinically, but the neural circuit mechanisms underlying the comorbid anxiety symptoms in pain (CASP) in context of chronic pain remain unclear. Using viral neuronal tracing in mice, we identified a previously unknown pathway whereby glutamatergic neurons from layer 5 of the hindlimb primary somatosensory cortex (S1) (Glu), a well-known brain region involved in pain processing, project to GABAergic neurons in the caudal dorsolateral striatum (GABA). In a persistent inflammatory pain model induced by complete Freund's adjuvant injection, enhanced excitation of the Glu→GABA pathway was found in mice exhibiting CASP. Reversing this pathway using chemogenetic or optogenetic approaches alleviated CASP. In addition, the optical activation of Glu terminals in the cDLS produced anxiety-like behaviors in naive mice. Overall, the current study demonstrates the putative importance of a novel Glu→GABA pathway in controlling at least some aspects of CASP.

Microglia in the Primary Somatosensory Barrel Cortex Mediate Trigeminal Neuropathic Pain.

Trigeminal neuropathic pain (TGN) is an attacking, abrupt, electric-shock headache involving abnormal cortical activity. The neural mechanism underlying TGN remains elusive. In this study, we explored the role of microglia in the primary somatosensory barrel cortex (S1BF), which is a critical region for TGN, of a mouse model of TGN that displayed significant pain-related behaviors. Using electrophysiological recordings, we found robust neuronal hyperactivity in glutamatergic neurons of S1BF (GluS1BF). Chemogenetic inhibition of GluS1BF neurons significantly relieved mechanical allodynia in TGN mice. In naïve mice, chemogenetic activation of GluS1BF neurons induced pain sensitization. In addition, we found that microglia in the S1BF (microgliaS1BF) were significantly activated, with density and morphology changes. Intraperitoneal administration of minocycline, a microglia inhibitor, attenuated pain sensitization, and decreased GluS1BF neuronal activity. Together, these findings demonstrate the putative importance of microglia as a key regulator in TGN through actions on GluS1BF neuronal adaptation.