Gebara, E. | Search bioRxiv

bioRxiv2022

Mitofusin-2 in nucleus accumbens D2-MSNs regulates social dominance and neuronal function

The nucleus accumbens (NAc) is a brain hub regulating motivated behaviors, including social competitiveness. Mitochondrial function in the NAc is critically implicated in the association between anxiety and social competitiveness, and the mitochondrial fusion protein mitofusin 2 (Mfn2) in NAc neurons has been shown to regulate anxiety-related behaviors. However, it remains unexplored whether accumbal Mfn2 levels also affect social behavior and whether Mfn2 actions in the emotional and social domain are driven by distinct cell types. Here, we found that subordinate-prone highly anxious rats show reduced accumbal Mfn2 levels and that Mfn2 overexpression promotes dominant behavior. In mice, selective Mfn2 downregulation in NAc dopamine D2 receptor-expressing medium spiny neurons (D2-MSNs) induced social subordination, accompanied by reduced mitochondrial function and decreased neuronal excitability. Instead, D1-MSN-targeted Mfn2 downregulation affected competitive ability only transiently mainly by increases in anxiety-like behaviors. Our results assign dissociable cell-type specific roles to Mfn2 in the NAc in modulating social dominance and anxiety.

neuroscience↗

bioRxiv2022

Engineered human cytokine/antibody fusion proteins expand regulatory T cells and confer autoimmune disease protection

Low dose human interleukin-2 (hIL-2) treatment is used clinically to treat autoimmune disorders due to the cytokines preferential expansion of immunosuppressive regulatory T cells (TRegs). However, high toxicity, short serum half-life, and off-target immune cell activation limit the clinical potential of IL-2 treatment. Recent work showed that complexes comprising hIL-2 and the anti-hIL-2 antibody F5111 overcome these limitations by preferentially stimulating TRegs over immune effector cells. Although promising, therapeutic translation of this approach is complicated by the need to optimize dosing ratios and by the instability of the cytokine/antibody complex. We leveraged structural insights to engineer a single-chain hIL-2/F5111 antibody fusion protein, termed F5111 immunocytokine (IC), that potently and selectively activates and expands TRegs. F5111 IC conferred protection in mouse models of colitis and checkpoint inhibitor-induced diabetes mellitus. These results provide a roadmap for IC design and establish a TReg-biased immunotherapy that could be clinically translated for autoimmune disease treatment.

bioengineering↗

bioRxiv2022

Involvement of prelimbic cortex neurons and related circuits in the acquisition of cooperative learning by pairs of rats

Social behaviors such as cooperation are crucial for mammals. A deeper knowledge of the neuronal mechanisms underlying cooperation can be beneficial for people suffering from pathologies with impaired social behavior. Our aim was to study the brain activity when two animals synchronize their behavior to obtain a mutual reinforcement. In a previous work, we showed that the activity of the prelimbic cortex (PrL) was enhanced during cooperation in rats, especially in the ones leading most cooperative trials (leader rats). In this study, we investigated the specific cell type/s in the PrL contributing to cooperative behaviors. To this end, we collected rats brains at key moments of the learning process to analyze the levels of c-FOS expression in the main cellular groups of the PrL (glutamatergic cells containing D1 and D2 receptors and interneurons). Leader rats showed increased c-FOS activity in cells expressing D1 receptors during cooperation. In addition, we analyzed the levels of anxiety, dominance, and locomotor behavior, finding that leader rats are in general less anxious and less dominant than followers. We also recorded local field potentials (LFPs) from the PrL, the nucleus accumbens septi (NAc), and the basolateral amygdala (BLA). Spectral analysis showed that delta activity in PrL and NAc increased when rats cooperated, while BLA activity in delta and theta bands decreased considerably during cooperation. The PrL and NAc also increased their connectivity in the high theta band during cooperation. Thus, the present work identifies the specific PrL cell types engaged in this behavior, as well as its connectivity with subcortical brain regions (BLA, NAc) during cooperation. Significance StatementBrain mechanisms underlying cooperative behaviors remain unknown. The present study identified specific neuronal types from the PrL cortex engaged in the acquisition of a cooperative task, as well as their connectivity with subcortical projection sites, such as the NAc and the BLA during cooperation. Rats leading the cooperation trials (designated leaders) presented an increased activation of D1-containing neurons in the PrL during cooperation. The PrL and NAc electrical activity increased when rats were cooperating, while the BLA activity increased before cooperation. The PrL and NAc showed increased functional connectivity at the moment of cooperation on the platform, whereas during the individual phase the highest connectivity was found before the animals climbed individually onto the platform.

neuroscience↗