Social disorders are a type of neurological and psychiatric disorder associated with humansvery highBehavioral disorders. Current research suggests that many nuclei and neural circuits are associated with social behavior, including the prefrontal cortex, basolateral amygdala, nucleus accumbens, ventral tegmental area, and lateral habenula (LHb). LHb serves as the "anti reward center" of the brain, receiving input from the limbic forebrain and basal ganglia, and primarily targeting the midbrain monoamine neural regulatory system. Due to its unique anatomical location, LHb plays a pivotal role in integrating reward, sensory, and experiential information, regulating various motivational, cognitive, and motor processes, and thus participating in the occurrence and development of various neurological and psychiatric disorders. In recent years, researchers have found that LHb plays a crucial role in social behavior. However, the molecular and cellular mechanisms by which LHb regulates social behavior, such as social anhedonia, are not yet clear, which is a major obstacle to understanding the pathological mechanisms of social anhedonia and translating current progress into effective clinical treatment through specific therapeutic targets.

On July 3, 2023, the latest collaboration between Professor Xu Xingshun's team from the Institute of Neuroscience at Soochow University and Professor Wang Guanghui's team from the School of Pharmacy at Soochow University was published online in the international journal Cell Reports under the title "Tet2 acts in the lateral habitua to regulate social preference in mice".

Screenshot of the online publication of the paper

So far, an increasing number of studies have shown that external environmental stress can affect individual behavior through epigenetic modifications of genes. The latest research confirms that hydroxymethylation is an important form of demethylation, and Ten Eleven Translocation (Tet2), as an important hydroxymethylation catalytic enzyme, affects gene transcription by regulating DNA hydroxymethylation modification (5hmC). The research team led by Professor Xu Xingshun and Professor Wang Guanghui from Soochow University conducted a study and discussion on this scientific issue.

The research team found that the hydroxymethyltransferase Tet2 is highly expressed in mouse LHb, and selective interference with Tet2 expression in LHb causes social preference disorders in mice. By analyzing the sequencing results of 5hmC modifications in the whole genome, it was found that Tet2 deletion induced DhMRs (differential hydroxymethylated regions) annotation genes are related to neuronal function (synaptic development and projection).

Figure 1: Tet2 deficient mice exhibit significant social preference disorders in a social animal model

To investigate the effect of Tet2 deficiency on neuronal activity, the team used a miniaturized two-photon microscope (FHIRM-TPM) to detect in vivo Ca2+activity in free acting mice. It was found that the calcium activity of LHb neurons in Tet2 deficient mice was significantly increased, suggesting that Tet2 deficiency increases LHb neuron activity. And further demonstrated that Tet2 mediates social preference behavior in mice by regulating the 5hmC modification of the autism related gene Sh3rf2.

Figure 2: Using miniaturized two-photon technology to reveal abnormal LHb neural activity in Tet2 deficient mice

This study first proposes the regulatory mechanism by which Tet2 dependent epigenetic modifications affect the electrical activity of LHb and participate in social preference behavior; Targeting Tet2 or its downstream signaling pathway significantly improved social preference disorders in Tet2 gene knockout mice. This study has identified new targets for the treatment of neurological and psychiatric disorders related to social behavior disorders.