Biology subjects

Lin, T.-C. E.

Publications and source records attributed to Lin, T.-C. E..

3 recordsLinked to original sources

bioRxiv2025

Sex Dependent Effects of Minocycline on Contextual Fear Memory

Recent studies have highlighted the crucial role of microglia in fear learning and memory. This supports the potential therapeutic value of the anti-inflammatory agent minocycline, which regulates microglial activity, in psychiatric disorders involving dysregulated emotional memory. To assess the impact of minocycline during a tractable intervention window, we examined its acute systemic effects on the reconsolidation, extinction, and forgetting of contextual fear memory (CFM) in rats. Our findings show that the effects of minocycline on fear memory and anxiety-like behaviours depend on sex, memory activation (i.e., whether it was retrieved), and memory age. In males with recently acquired CFM, minocycline given before retrieval enhanced extinction and reduced fear expression. When administered without retrieval, it disrupted passive forgetting, increasing evoked fear behaviour. This extinction-enhancing effect did not occur with older (28-day) memories rather it strengthened CFM through enhancing reconsolidation. In contrast, in females, minocycline increased the expression of recent fear memories regardless of retrieval, without affecting extinction or forgetting. This elevated fear expression appeared linked to heightened anxiety-like behaviour. These findings suggest that minocycline, or other microglia-targeting agents, would need to be used in a highly selective and targeted manner to therapeutically modulate pathological fear memories. Minocycline may be beneficial as an adjunct to exposure therapy in men explicitly retrieving recent fear or trauma-related memories, but outside these conditions, it may worsen fear expression. These results help explain the mixed findings from therapeutic trials using minocycline in psychiatry and support the application of a more precision approach in any future applications.

animal behavior and cognition↗

bioRxiv2020

Neurotrophin receptor activation rescues cognitive and synaptic abnormalities caused by mutation of the psychiatric risk gene Cacna1c

Genetic variation in CACNA1C, which encodes the alpha-1 subunit of CaV1.2 L-type voltage-gated calcium channels, is strongly linked to risk for psychiatric disorders including schizophrenia and bipolar disorder. To translate genetics to neurobiological mechanisms and rational therapeutic targets, we investigated the impact of altered Cacna1c dosage on rat cognitive, synaptic and circuit phenotypes implicated by patient studies. We show that rats hemizygous for Cacna1c harbor marked impairments in learning to disregard non-salient stimuli, a behavioral change previously associated with psychosis. This behavioral deficit is accompanied by dys-coordinated network oscillations during learning, pathway-selective disruption of hippocampal synaptic plasticity, attenuated Ca2+ signaling in dendritic spines and decreased signaling through the Extracellular-signal Regulated Kinase (ERK) pathway. Activation of the ERK pathway by a small molecule agonist of TrkB/TrkC neurotrophin receptors rescued both behavioral and synaptic plasticity deficits in Cacna1c+/- rats. These results map a route through which genetic variation in CACNA1C can disrupt experience-dependent synaptic signaling and circuit activity, culminating in cognitive alterations associated with psychiatric disorders. Our findings highlight targeted activation of neurotrophin signaling pathways with BDNF mimetic drugs as a novel, genetically informed therapeutic approach for rescuing behavioral abnormalities in psychiatric disorder. One Sentence SummaryNeurotrophin receptor activation reveals that BDNF mimetic drugs have therapeutic potential to ameliorate genetic risk for psychiatric disorders.

neuroscience↗

bioRxiv2018

Cyfip1 haploinsufficiency is associated with white matter changes, myelin thinning, reduction of mature oligodendrocytes and behavioural inflexibility

The biological basis of the increased risk for psychiatric disorders due to the pathogenic 15q11.2 copy number deletion is unknown. Previous work has shown disturbances in white matter tracts in human carriers of the deletion at this locus. Using a novel rat model, we have recapitulated low dosage of the candidate risk gene CYFIP1 present within the 15q11.2 interval to reveal alterations in white matter microstructure. Using diffusion tensor imaging, we first showed extensive white matter changes in Cyfip1 mutants that were most pronounced in the corpus callosum and external capsule. Transmission electron microscopy showed that these changes were associated with thinning of the myelin sheath in the corpus callosum. Myelin thinning was independent of changes in axon number or diameter but was associated with a reduction in the number of mature oligodendrocytes. Finally, we demonstrated functional effects on cognitive phenotypes sensitive to both disruptions in myelin and callosal circuitry.

neuroscience↗