Biology subjects

Meyza, K.

Publications and source records attributed to Meyza, K..

3 recordsLinked to original sources

bioRxiv2025

The Role of TCF7L2 in Regulating Energy Metabolism in Thalamocortical Circuitry and its Broader Impact on Social Behavior

Psychiatric and metabolic disorders often co-occur. While shared genetic factors and cellular dysfunctions are implicated, the underlying molecular mechanisms remain poorly understood. TCF7L2, a risk gene for type 2 diabetes and autism spectrum disorder, is highly expressed in the thalamus--a brain region extensively interconnected with the cortex, playing a key role in sensory processing, motor control, and behavioral regulation. Given its known role as a transcription factor regulating systemic energy metabolism, we explored its potential contribution to brain metabolism and behavior. To this end, we used a conditional knockout model with postnatal TCF7L2 loss in the thalamus and partial deficiency in the pancreas. Tcf7l2 knockout mice exhibited social deficits and reduced motor habituation. In parallel, they also developed systemic glucose intolerance, modelling the psychiatric-metabolic comorbidity. Thalamic depletion of TCF7L2 resulted in elevated inhibitory phosphorylation of the pyruvate dehydrogenase --an enzymatic gatekeeper for pyruvate utilization in energy production--in the thalamus and cortex. This was accompanied by altered thalamic and cortical metabolism, characterized by reduced efficiency of pyruvate oxidation alongside enhanced oxidation of fatty acids and ketone bodies. Notably, a ketogenic diet alleviated metabolic dysregulation in the brain and normalized some social behaviors in knockout mice. These findings suggest that impaired energy metabolism in the thalamocortical circuitry may represent one of the pathogenic mechanisms underlying neuropsychiatric symptoms.

neuroscience↗

bioRxiv2020

c-Fos-MMP-9 pathway in central amygdala mediates approach motivation but not reward consumption

Although impaired motivational and consummatory aspects of reward behavior are core symptoms of several psychiatric disorders, the underlying neural and molecular mechanisms remain poorly understood. c-Fos, as a component of AP-1 transcription factor, regulates the expression of matrix metalloproteinase 9 (MMP-9), an enzyme involved in synaptic remodeling and plasticity. Both proteins are expressed in the central amygdala (CeA) that orchestrates appetitive and aversive responses. We have examined the role of c-Fos and MMP-9 in CeA in reward and punishment processing. We have manipulated c-Fos and MMP-9 levels in vivo using: RNAi-based approach to block c-Fos expression, inhibitor-releasing nanoparticles to block MMP-9 activity, and lentiviral vector to increase MMP-9 expression. To assess motivation, consumption and learning reinforced by either a sweet or bitter-tasting solution, we employed automated behavioral tests in the IntelliCage cystem. We have used transgenic mouse lines to identify CeA cells expressing c-Fos and a specific fluorescently labelled substrate peptide to measure MMP-9 activity. Excitability of neurons was measured with patch-clamp. Blocking c-Fos expression has been found to disrupt both reward processing components, motivational and consummatory, while inhibition of MMP-9 activity has impaired only motivational aspects of the behavior. On the other hand, punishment processing has not been affected by those manipulations. Furthermore, we have observed that reward training induces c-Fos expression in both somatostatin (SST)+, and SST-neurons, while MMP-9 activity is increased in SST- subpopulation only. We have further linked SST+ population to consummatory reactions by showing that reward consumption increases excitability of the SST+ neurons. These findings reveal molecular mechanisms of motivational anhedonia, linking it to c-Fos-MMP-9 pathway and CeA SST- neurons, and consummatory anhedonia, linking it to c-Fos and CeA SST+ neurons.

neuroscience↗

bioRxiv2020

More than a feeling: central amygdala mediates social transfer of information about proximity of danger

To survive, an animal must adequately respond to challenges presented by the environment. Social animals can learn about danger from fear of conspecifics which allows them to avoid predation and other threats without costly, first-hand experience. However, it remains unclear as to whether animals can transmit specific information that helps an individual avoid harm or whether the transmitted social signals simply increase vigilance in a non-specific manner. Here we demonstrate that animals can select appropriate defensive strategies in a novel environment depending on cues from the conspecific and, using opsins targeted to behaviorally activated neurons, identify distinct neuronal circuits in the central amygdala (CeA) that are crucial for choosing a context-appropriate reaction. The identified circuits differ in molecular markers and patterns of connectivity. Thus, we show that social signals carry explicit information about proximity of danger, necessary for choosing a context-appropriate reaction, and that the choosing process is mediated by the CeA circuits.

neuroscience↗