Biology subjects

Lichtman, A. H.

Publications and source records attributed to Lichtman, A. H..

3 recordsLinked to original sources

bioRxiv2026

Colon-to-hind paw cross-organ sensitization is partially mediated by TrkB.T1-facilitated spinal neuroinflammation to activate lumbar DRG neurons

Patients with bowel disease can develop referred somatic pain at a later time with unknown molecular mechanisms. Using experimental mice with colitis induced by intracolonic installation of 2,4,6-Trinitrobenzenesulfonic acid (TNBS), we find an increase in the percentage of hind paw primary afferent neurons expressing Piezo2 or calcitonin gene-related peptide (CGRP), which are attenuated by TrkB.T1 knockout (KO). Concomitantly, TrkB.T1 KO also attenuates colitis-induced hind paw mechanical hypersensitivity and pain. Next, we find that TrkB.T1 is expressed in spinal cord astrocytes and its expression level is increased by colitis. TrkB.T1 KO reduces colitis-induced upregulation of Tumor necrosis factor-alpha (TNF-) mRNA but not upregulation of interleukin (IL)-6 mRNA in the spinal cord. Using calcium (Ca2+) imaging and ex vivo approaches, we find that TNF- elicits Ca2+ transients in capsaicin-sensitive as well as capsaicin-insensitive DRG neurons, and increases Piezo2 and CGRP expression in DRG neurons via distinct signaling pathways. Notably, TNF-or colitis-induced Piezo2 upregulation in L4 DRG neurons is mediated by or associated with the PI3K/Akt pathway that does not participate in CGRP upregulation. In contrast, CGRP upregulation in hind paw primary afferent neurons is associated with an upregulation of phosphorylated cAMP response element binding protein (p-CREB). Finally, we find that TrkB.T1 KO does not change the expression level of transient receptor potential cation channel subfamily V member 1 (TrpV1) in L4 DRG in colitis, explaining the ineffectiveness of TrkB.T1 KO on colitis-induced hind paw thermal hyperalgesia. These results suggest complex and distinct molecular pathways in colitis-induced somatic pain modalities and provide information for specific pain modality management.

neuroscience↗

bioRxiv2025

Meta-analysis of the brain transcriptomes of multiple genetic mouse models of schizophrenia highlights dysregulation in striatum and thalamus

Schizophrenia is a severe mental illness with high heritability, but its underlying mechanisms are poorly understood. We meta-analyzed large-scale brain transcriptomic data from mice harboring individual loss-of-function mutations in seven schizophrenia risk genes (Akap11, Dagla, Gria3, Grin2a, Sp4, Srrm2, Zmym2). While all studied brain regions were affected, the striatum and the thalamus emerged as key brain regions of convergence. Striatum showed downregulation of synapse-and oxidative phosphorylation-related gene sets in all models. In the thalamus, mutants separated into two groups based on transcriptomic phenotype: synapse-related gene sets were upregulated in mutants with only schizophrenia and bipolar association, and were downregulated in mutants that are associated with developmental delay/intellectual disability in addition to schizophrenia. Overall, our meta-analysis reveals convergence and divergence in brain transcriptomic phenotype in these schizophrenia genetic models, supports the involvement of striatal disturbance and synapse dysfunction in schizophrenia, and points to a key role of the thalamus.

neuroscience↗

bioRxiv2024

Cannabinoid receptor 1 positive allosteric modulator ZCZ011 shows differential effects on behavior and the endocannabinoid system in HIV-1 Tat transgenic female and male mice

The cannabinoid receptor type 1 (CB1R) is a promising therapeutic target for various neurodegenerative diseases, including HIV-1-associated neurocognitive disorder (HAND). However, the therapeutic potential of CB1R by direct activation is limited due to its psychoactive side effects. Therefore, research has focused on indirectly activating the CB1R by utilizing positive allosteric modulators (PAMs). Studies have shown that CB1R PAMs (ZCZ011 and GAT211) are effective in mouse models of Huntingtons disease and neuropathic pain, and hence, we assess the therapeutic potential of ZCZ011 in a well-established mouse model of neuroHIV. The current study investigates the effect of chronic ZCZ011 treatment (14 days) on various behavioral paradigms and the endocannabinoid system in HIV-1 Tat transgenic female and male mice. Chronic ZCZ011 treatment (10 mg/kg) did not alter body mass, locomotor activity, or anxiety-like behavior regardless of sex or genotype. However, differential effects were noted in hot plate latency, motor coordination, and recognition memory in female mice only, with ZCZ011 treatment increasing hot plate latency and improving motor coordination and recognition memory. Only minor effects or no alterations were seen in the endocannabinoid system and related lipids except in the cerebellum, where the effect of ZCZ011 was more pronounced in female mice. Moreover, AEA and PEA levels in the cerebellum were positively correlated with improved motor coordination in female mice. In summary, these findings indicate that chronic ZCZ011 treatment has differential effects on antinociception, motor coordination, and memory, based on sex and HIV-1 Tat expression, making CB1R PAMs potential treatment options for HAND without the psychoactive side effects.

neuroscience↗