Author Correction: Postsynaptic lncRNA Sera/Pkm2 pathway orchestrates the transition from social competition to rank by remodeling the neural ensemble in mPFC
Related Articles
Frontostriatal regulation of brain circuits contributes to flexible decision making
Deficits in behavioral or cognitive flexibility that are linked to altered activity in both cortical and subcortical brain regions, are often observed across multiple neuropsychiatric disorders. The medial prefrontal cortex (mPFC)-nucleus accumbens (NAc) pathway in rats plays a critical role in flexible control of behavior. However, the modulation of this pathway on activity and functional connectivity with the rest of the brain remains unclear. In this study, we first confirmed the role of the mPFC-NAc pathway in behavioral flexibility using a set-shifting task in rats and then evaluated the causal effects of mPFC-NAc activation induced by chemogenetic stimulation of the terminal axons of the NAc with DREADD expression on whole-brain activity and functional connectivity measured by functional MRI. mPFC-NAc activation improved performance on the set-shifting task by reducing perseverative errors. Additionally, stimulation of this pathway increased activity in a set of brain regions within the basal ganglia-thalamus-cortical loop network including NAc, thalamus, hypothalamus and various connected cortical regions, while also decreased functional connectivity strength of NAc-mPFC, NAc-secondary motor cortex (M2), and various cortical circuits. Moreover, performance on the set-shifting task was related to the functional connectivity strength of the above frontostriatal and cortical circuits. These findings provide insights into the link between specific frontostriatal circuits on decision making flexibility, which may inform potential future interventions for behavioral flexibility deficits.
mPFC DCC coupling with CaMKII+ neuronal excitation participates in behavioral despair in male mice
A longed lack of control over harmful stimuli can lead to learned helplessness (LH), a significant factor in depression. However, the cellular and molecular mechanisms underlying LH, and eventually behavioral despair, remain largely unknown. The deleted in colorectal cancer (dcc) gene is associated with the risk of depression. However, the therapeutic potential and regulation mechanism of DCC in behavioral despair are still uncertain. In this study, we showed that depressive stimulators, including LH, lipopolysaccharide, and unpredictable chronic mild stress, triggered an elevation in DCC expression in the medial prefrontal cortex (mPFC). Additionally, elevated DCC expression in the mPFC was crucial in inducing behavioral despair, as evidenced by the induction of behavioral despair in normal mice and exacerbation of behavioral despair in LH mice upon DCC overexpression. By contrast, neutralizing DCC activity ameliorated LH-induced behavioral despair. Importantly, we elucidated that pathological DCC expression was attributable to the excessive excitation of CaMKII+ neurons in a manner dependent on the calpain-mediated degradation of SCOP and aberrant phosphorylation of the ERK signaling pathway. In addition, the increase in DCC expression led to a decreased excitability threshold in CaMKII+ neurons in the mPFC, which was supported by the observation that the ligand netrin 1 increased the frequency of action potential firing and of spontaneous excitatory postsynaptic currents in CaMKII+ neurons. In conclusion, our data indicate that LH triggers the excessive excitation of CaMKII+ neurons and activation of calpain-SCOP/ERK signaling to promote DCC expression, and DCC represents a crucial target for the treatment of LH-induced behavioral despair in male mice.
Historical loss weakens competitive behavior by remodeling ventral hippocampal dynamics
Competitive interactions are pervasive within biological populations, where individuals engage in fierce disputes over vital resources for survival. Before the establishment of a social hierarchy within the population, this competition becomes even more intense. Historical experiences of competition significantly influence the competitive performance; individuals with a history of persistent loss are less likely to initiate attacks or win escalated contests. However, it remains unclear how historical loss directly affects the evolution of mental processes during competition and alters responses to ongoing competitive events. Here, we utilized a naturalistic food competition paradigm to track the competitive patterns of mutually unfamiliar competitors and found that a history of loss leads to reduced competitive performance. By tracking the activity of ventral hippocampal neuron ensembles, we identified clusters of neurons that responded differently to behavioral events during the competition, with their reactivity modulated by previous losses. Using a Recurrent Switch Linear Dynamical System (rSLDS), we revealed rotational dynamics in the ventral hippocampus (vHPC) during food competition, where different discrete internal states corresponded to different behavioral strategies. Moreover, historical loss modulates competitive behavior by remodeling the characteristic attributes of this rotational dynamic system. Finally, we found that an evolutionarily conserved glutamate receptor-associated protein, glutamate receptor-associated protein 1 (Grina), plays an important role in this process. By continuously monitoring the association between the attributes of the dynamic system and competitiveness, we found that restoring Grina expression effectively reversed the impact of historical loss on competitive performance. Together, our study reveals the rotational dynamics in the ventral hippocampus during competition and elucidates the underlying mechanisms through which historical loss shapes these processes.
SIRT3-PINK1-PKM2 axis prevents osteoarthritis via mitochondrial renewal and metabolic switch
Maintaining mitochondrial homeostasis is critical for preserving chondrocyte physiological conditions and increasing resistance against osteoarthritis (OA). However, the underlying mechanisms governing mitochondrial self-renewal and energy production remain elusive. In this study, we demonstrated mitochondrial damage and aberrant mitophagy in OA chondrocytes. Genetically overexpressing PTEN-induced putative kinase 1 (PINK1) protects against cartilage degeneration by removing defective mitochondria. PINK1 knockout aggravated cartilage damage due to impaired mitophagy. SIRT3 directly deacetylated PINK1 to promote mitophagy and cartilage anabolism. Specifically, PINK1 phosphorylated PKM2 at the Ser127 site, preserving its active tetrameric form. This inhibited nuclear translocation and the interaction with β-catenin, resulting in a metabolic shift and increased energy production. Finally, a double-knockout mouse model demonstrated the role of the SIRT3-PINK1-PKM2 axis in safeguarding the structural integrity of articular joints and improving motor functions. Overall, this study provides a novel insight into the regulation of mitochondrial renewal and metabolic switches in OA.
Stress-induced GHS-R1a expression in medial prefrontal cortical neurons promotes vulnerability to anxiety in mice
The neural basis of anxiety is unclear, which hinders the treatment of anxiety disorders. Here, we found that αCaMKII+ neurons in the medial prefrontal cortex (mPFCαCaMKII+) responded to stressors with increased activity both under physiological conditions and after repeated restraint stress (RRS) in mice. Chemogenetic activation of mPFCαCaMKII+ neurons ameliorated stress-induced anxiety. A delayed increase in the expression of growth hormone secretagogue receptor 1a (GHS-R1a), the receptor of the peripheral metabolic hormone ghrelin, in mPFCαCaMKII+ neurons coincided with reduced excitatory synaptic transmission and the development of RRS-induced enhancement of anxiety-related behavior. Virus-mediated GHS-R1a upregulation in mPFCαCaMKII+ neurons exaggerated the excitation/inhibition (E/I) imbalance and promoted anxiety-related behavior, whereas GHS-R1a knockdown had the opposite effect. We conclude that GHS-R1a signaling contributes to the development of stress-induced anxiety by shaping synaptic activity of mPFCαCaMKII+ neurons. GHS-R1a may be a new therapeutic target for treating anxiety disorders.
Responses