Long-term depression (LTD) at the parallel fiber (PF)-to-cerebellar Purkinje cell (PC) synapse is implicated in the output of PCs, the sole output of the cerebellar cortex. In addition to synaptic plasticity, intrinsic excitability is also one of the components that determines PC output. Although long-term potentiation of intrinsic excitability (LTP-IE) has been suggested, it has yet to be investigated how PF–PC LTD modifies intrinsic excitability of PCs. Here, we show that pairing of the PF and climbing fiber (CF) for PF–PC LTD induction evokes LTD-IE in cerebellar PCs from male C57BL/6 mice. Interestingly, this intrinsic plasticity showed different kinetics from synaptic plasticity, but both forms of plasticity share Ca²⁺ signaling and protein kinase C pathway as their underlying mechanism. Although small-conductance Ca²⁺-activated K⁺ channels play important roles in LTP-IE, no direct implication has been found. After PF–PC LTD induction, neither the temporal summation of dendritic EPSP nor the power of spike frequency adaptation is changed, indicating that cerebellar LTD executes the information processing in a quantitative way without quality changes of synaptic integration and generation of output signals. Our results suggest that LTD-IE may have a synergistic effect with synaptic depression on the total net output of neurons by amplifying the modification of PF synaptic transmission. SIGNIFICANCE STATEMENT Although the output of Purkinje cells (PCs) is a critical component of cerebellum-dependent learning and memory, the changes of PC excitability when synaptic LTD occurs are unclear. Here, we show that the induction of PF–PC LTD evokes LTD-IE in PCs. Our observation complements previous intrinsic plasticity phenomenon of long-term potentiation of intrinsic excitability (LTP-IE), providing evidence for the idea that intrinsic plasticity has bidirectionality as synaptic plasticity. LTD-IE occurs together with synaptic LTD and both phenomena are dependent on the Ca²⁺ signaling pathway. Furthermore, our findings raise the prospect that this synaptic and intrinsic plasticity acts synergistically in PCs to modify neuronal activity in the same direction when learning occurs.

For survival, it is crucial for eating behaviours to be sequenced through two distinct seeking and consummatory phases. Heterogeneous lateral hypothalamus (LH) neurons are known to regulate motivated behaviours, yet which subpopulation drives food seeking and consummatory behaviours have not been fully addressed. Here, in male mice, fibre photometry recordings demonstrated that LH leptin receptor (LepR) neurons are correlated explicitly in both voluntary seeking and consummatory behaviours. Further, micro-endoscope recording of the LH^LepR neurons demonstrated that one subpopulation is time-locked to seeking behaviours and the other subpopulation time-locked to consummatory behaviours. Seeking or consummatory phase specific paradigm revealed that activation of LH^LepR neurons promotes seeking or consummatory behaviours and inhibition of LH^LepR neurons reduces consummatory behaviours. The activity of LH^LepR neurons was increased via Neuropeptide Y (NPY) which acted as a tonic permissive gate signal. Our results identify neural populations that mediate seeking and consummatory behaviours and may lead to therapeutic targets for maladaptive food seeking and consummatory behaviours.

Atherosclerosis is closely related to vascular dysfunction and hypertension. Ojeoksan (OJS), originally recorded in an ancient Korean medicinal book named “Donguibogam”, is a well-known, blended herbal formula. This study was carried out to investigate the beneficial effects of OJS on atherosclerosis in vitro and in vivo. Western-diet-fed apolipoprotein-E gene-deficient mice (ApoE −/−) were used for this study for 16 weeks, and their vascular dysfunction and inflammation were analyzed. OJS-treated ApoE −/− mice showed lowered blood pressure and glucose levels. The levels of metabolic parameters with hyperlipidemia attenuated following OJS administration. Hematoxylin and eosin (H&E) staining revealed that treatment with OJS reduced atherosclerotic lesions. OJS also suppressed the expression of adhesion molecules and matrix metalloproteinases (MMPs) compared to Western-diet-fed ApoE −/− mice and tumor necrosis factor-alpha (TNF-α)-stimulated human umbilical vein endothelial cells (HUVECs). Expression levels of MicroRNAs (miRNA)-10a, -126 3p were increased in OJS-fed ApoE −/− mice. OJS significantly increased the phosphorylation of endothelial nitric oxide synthase (eNOS) and protein kinase B (Akt), which are involved in nitric oxide (NO) production. OJS also regulated eNOS coupling by increasing the expression of endothelial GTP Cyclohydrolase-1 (GTPCH). Taken together, OJS has a protective effect on vascular inflammation via eNOS coupling-mediated NO production and might be a potential therapeutic agent for both early and advanced atherosclerosis.

RAS/MAPK pathway mutations often induce RASopathies with overlapping features, such as craniofacial dysmorphology, cardiovascular defects, dermatologic abnormalities, and intellectual disabilities. Although B-Raf proto-oncogene ( BRAF ) mutations are associated with cardio-facio-cutaneous (CFC) syndrome and Noonan syndrome, it remains unclear how these mutations impair cognition. Here, we investigated the underlying neural mechanisms using several mouse models harboring a gain-of-function BRAF mutation (K499E) discovered in RASopathy patients. We found expressing BRAF K499E (KE) in neural stem cells under the control of a Nestin-Cre promoter (Nestin;BRAF ^KE/+ ) induced hippocampal memory deficits, but expressing it in excitatory or inhibitory neurons did not. BRAF KE expression in neural stem cells led to aberrant reactive astrogliosis, increased astrocytic Ca ²⁺ fluctuations, and reduced hippocampal long-term depression (LTD) in mice. Consistently, 3D human cortical spheroids expressing BRAF KE also showed reactive astrogliosis. Astrocyte-specific adeno-associated virus–BRAF KE (AAV-BRAF KE) delivery induced memory deficits and reactive astrogliosis and increased astrocytic Ca ²⁺ fluctuations. Notably, reducing extracellular signal-regulated kinase (ERK) activity in astrocytes rescued the memory deficits and altered astrocytic Ca ²⁺ activity of Nestin;BRAF ^KE/+ mice. Furthermore, reducing astrocyte Ca ²⁺ activity rescued the spatial memory impairments of BRAF KE–expressing mice. Our results demonstrate that ERK hyperactivity contributes to astrocyte dysfunction associated with Ca ²⁺ dysregulation, leading to the memory deficits of BRAF -associated RASopathies.