In cortical neurons and hippocampal slice cultures, blocking mitochondrial pyruvate uptake rewires metabolism to increase reliance on glutamate to fuel the TCA cycle. This diminishes the readily releasable pool of neuronal glutamate and minimizes the positive-feedback cascade of excitotoxic injury.

Summary Flexibly adapting to novel situations is critical for survival, which is impaired in neuropsychiatric disorders 1 . Thus, understanding whether and how novelty prepares, or primes, brain circuitry to facilitate cognitive flexibility has important translational relevance. Novelty recruits the hippocampus and medial prefrontal cortex (mPFC) 2 and may prime hippocampal-prefrontal circuitry for subsequent learning-associated plasticity. We find that novelty resets ventral hippocampal-prefrontal (vHPC-mPFC) circuitry and facilitates overcoming an established strategy. Exposing mice to novelty disrupted a previously encoded strategy by reorganizing vHPC activity to local theta (4–12 Hz) oscillations and weakening existing vHPC-mPFC connectivity. As mice subsequently adapted to a new task, vHPC neurons developed new task-associated activity, vHPC-mPFC connectivity was strengthened, and mPFC neurons updated encoding with new rules. Without novelty, mice adhered to their established strategy. Blocking dopamine D1-receptors (D1Rs) or inhibiting novelty-tagged cells expressing D1Rs in the vHPC prevented these behavioral and physiological effects of novelty. Further, D1R activation mimicked the effects of novelty. These results suggest that novelty promotes adaptive learning by D1R-mediated resetting of vHPC-mPFC circuitry, thereby enabling learning-associated circuit plasticity.

Experience-dependent expression of immediate-early gene transcription factors (IEG-TFs) can transiently change the transcriptome of active neurons and initiate persistent changes in cellular function. However, the impact of IEG-TFs on circuit connectivity and function is poorly understood. We investigate the specificity with which the IEG-TF NPAS4 governs experience-dependent changes in inhibitory synaptic input onto CA1 pyramidal neurons (PNs). We show that novel sensory experience selectively enhances somatic inhibition mediated by cholecystokinin-expressing basket cells (CCKBCs) in an NPAS4-dependent manner. NPAS4 specifically increases the number of synapses made onto PNs by individual CCKBCs without altering synaptic properties. Additionally, we find that sensory experience-driven NPAS4 expression enhances depolarization-induced suppression of inhibition (DSI), a short-term form of cannabinoid-mediated plasticity expressed at CCKBC synapses. Our results indicate that CCKBC inputs are a major target of the NPAS4-dependent transcriptional program in PNs and that NPAS4 is an important regulator of plasticity mediated by endogenous cannabinoids.

Visual Abstract

Cholinergic interneurons (CINs) in the striatum respond to salient stimuli with a multiphasic response, including a pause, in neuronal activity. Slice physiology experiments have shown the importance of dopamine D2 receptors (D2Rs) in regulating CIN pausing yet the behavioral significance of the CIN pause and its regulation by dopamine in vivo is still unclear. Here, we show that D2R upregulation in CINs of the nucleus accumbens (NAc) lengthens the pause in CIN activity ex vivo and enlarges a stimulus-evoked decrease in acetylcholine (ACh) levels during behavior. This enhanced dip in ACh levels is associated with a selective deficit in the learning to inhibit responding in a Go/No-Go task. Our data demonstrate, therefore, the importance of CIN D2Rs in modulating the CIN response induced by salient stimuli and point to a role of this response in inhibitory learning. This work has important implications for brain disorders with altered striatal dopamine and ACh function, including schizophrenia and attention-deficit hyperactivity disorder (ADHD).