Biology subjects

Jimenez-Fernandez, L.

Publications and source records attributed to Jimenez-Fernandez, L..

3 recordsLinked to original sources

bioRxiv2026

SEROTONERGIC ANXIETY IS A STRESS INTENSITY-DEPENDENT STATE MEDIATED BY DOPAMINERGIC SIGNALING

Despite the central role attributed to serotonin in anxiety, its involvement and therapeutic efficacy are inconsistent, raising the possibility that serotonergic recruitment depends on the stress history from which anxiety emerges. Using larval zebrafish, we combined graded glucocorticoid exposure with chemogenetic DRN manipulation, whole-brain activity mapping, and pharmacology to test whether stress intensity determines serotonergic involvement in anxiety.Increasing stress intensity did not simply increase anxiety severity but generated distinct anxiety phenotypes. Lower glucocorticoid exposure produced context-general anxiety that required the serotonergic DRN, whereas higher exposure produced context-dependent, DRN-independent anxiety. Whole-brain mapping identified a posterior tubercular/hypothalamic dopaminergic region associated with DRN-dependent anxiolysis, while D1, but not D2 receptor antagonism abolished the anxiolytic effect of DRN ablation. Finally, environmentally relevant nanomolar concentrations of methylphenidate reduced anxiety-like behavior, further supporting dopaminergic modulation of anxiety. Together, our findings identify stress intensity as a determinant of serotonergic recruitment during anxiety, reveal a downstream contribution of D1-dependent dopaminergic signaling, and provide a framework for understanding the mechanistic heterogeneity of anxiety and its variable response to serotonergic treatments.

neuroscience↗

bioRxiv2026

Organization, development, and plasticity of the serotonergic dorsal raphe nucleus projectome

The dorsal raphe nucleus (DRN) is the main source of serotonin (5-HT) in the central nervous system. 5-HT DRN neurons modulate a wide range of physiological functions and brain states via their widespread and heterogeneous projections. Yet the organizational logic, developmental dynamics, and experience-dependent plasticity of these projections remain poorly understood. By reconstructing the whole brain projections of 81 individual 5-HT DRN neurons across developmental stages in the larval zebrafish, we find that these neurons exhibit diverse projection patterns, ranging from broadly distributed to spatially confined. We identify two previously uncharacterized, projection-defined subpopulations within the larval dorsal raphe nucleus, which selectively target either the telencephalon or the spinal cord. This organization is consistent with the existence of anatomically distinct serotonergic pathways that may differentially influence forebrain and sensorimotor circuits. Longitudinal analysis revealed that the gross architecture of 5-HT neurons remained stable during larval development, although region-specific remodeling occurred in all neurons. Importantly, stress exposure during the first week of development, but not thereafter, altered the density of 5-HT DRN projections to telencephalic regions, suggesting a critical window of increased plasticity during early life. Collectively, our findings clarify the developmental trajectory, maturation, and stress-induced plasticity of the serotonergic circuitry, providing important insights for deciphering the pathophysiology of stress-related mental disorders.

neuroscience↗

bioRxiv2023

mPD5, an efficacious PICK1 inhibitor for treating chronic pain

Chronic pain is a complex, debilitating, and escalating health problem worldwide, impacting one in five adults. Current treatment is compromised by dose-limiting side effects including high abuse liability, loss of ability to function socially and professionally, fatigue, drowsiness, and apathy. PICK1 has emerged as a promising target for the treatment of chronic pain conditions. Here, we develop and characterize a cell-permeable fatty acid conjugated bivalent peptide inhibitor of PICK1 and assess its effects on acute and chronic pain. The myristoylated myr-NPEG4-(HWLKV)2, (mPD5), self-assembles into core-shell micelles that provide favourable pharmacodynamic properties and relieves ongoing and evoked mechanical hypersensitivity, thermal hypersensitivity as well as anxio-depressive symptoms in mouse models of neuropathic and inflammatory pain following subcutaneous administration. No overt no side effects were associated with mPD5 administration, and it has no effect on acute nociception. Finally, neuropathic pain is relieved far into the chronic phase (18 weeks post SNI surgery) and while the effect of a single injection ceases after a few hours, repeated administration provides pain relief lasting up to 20 hours after the last injection.

pharmacology and toxicology↗