Adrenergic signalling to astrocytes in anterior cingulate cortex contributes to pain-related aversive memory in rats.

Pain contains both sensory and affective dimensions. We identify the role of norepinephrine in colorectal distention (sub-threshold for acute pain) induced conditioned place avoidance and plasticity gene expression in the anterior cingulate cortex (ACC). Activating locus coeruleus (LC)-projecting ACC neurons facilitates pain-evoked aversive consolidation and memory, while inhibiting LC-projecting ACC neurons reversibly blocks it. Optogenetic activation of ACC astrocytes facilitates aversive behaviour. ACC astrocytic Gi manipulation suppressed aversive behaviour and early plasticity gene expression induced by opto-activation of LC neurons projecting to ACC. Evidences for the critical role of ß2AR in ACC astrocytes were provided using AAV encoding ß2AR miRNAi to knockdown ß2AR in astrocytes. In contrast, opto-activation of ACC astrocytic ß2ARs promotes aversion memory. Our findings suggest that projection-specific adrenergic astrocytic signalling in ACC is integral to system-wide neuromodulation in response to visceral stimuli, and plays a key role in mediating pain-related aversion consolidation and memory formation.

ß2-Adrenoceptors in the Medial Prefrontal Cortex Excitatory Neurons Regulate Anxiety-like Behavior in Mice.

The medial prefrontal cortex (mPFC) and ß-adrenoceptors (ßARs) have been implicated in modulating anxiety-like behavior. However, the specific contributions of the ß2-AR subtype in mPFC in anxiety are still unclear. To address this issue, we used optogenetic and microRNA-based (miRNA) silencing to dissect the role of ß2-AR in mPFC in anxiety-like behavior. On the one hand, we use a chimeric rhodopsin/ß2-AR (Opto-ß2-AR) with in vivo optogenetic techniques to selectively activate ß2-adrenergic signaling in excitatory neurons of the mPFC. We found that opto-activation of ß2-AR is sufficient to induce anxiety-like behavior and reduce social interaction. On the other hand, we utilize the miRNA silencing technique to specifically knock down the ß2-AR in mPFC excitatory neurons. We found that the ß2-AR knock down induces anxiolytic-like behavior and promotes social interaction compared to the control group. These data suggest that ß2-AR signaling in the mPFC has a critical role in anxiety-like states. These findings suggest that inhibiting of ß2-AR signaling in the mPFC may be an effective treatment of anxiety disorders.

Trigeminal neuropathy causes hypomyelination in the anterior cingulate cortex, disrupts the synchrony of neural circuitry, and impairs decision-making in male rats.

Infraorbital nerve-chronic constriction injury (ION-CCI) has become the most popular chronic trigeminal neuropathic pain (TNP) injury animal model which causes prolonged mechanical allodynia. Accumulative evidence suggests that TNP interferes with cognitive functions, however the underlying mechanisms are not known. The aim of this study was to investigate decision-making performance as well as synaptic and large-scale neural synchronized alterations in the spinal trigeminal nucleus (SpV) circuitry and anterior cingulate cortex (ACC) neural circuitry in male rats with TNP. Rat gambling task showed that ION-CCI led to decrease the proportion of good decision makers and increase the proportion of poor decision makers. Electrophysiological recordings showed long-lasting synaptic potentiation of local field potential in the trigeminal ganglia-SpV caudalis (SpVc) synapses in TNP rats. In this study, TNP led to disruption of ACC spike timing and basolateral amygdala (BLA) theta oscillation associated with suppressed synchronization of theta oscillation between the BLA and ACC, indicating reduced neuronal communications. Myelination is critical for information flow between brain regions, and myelin plasticity is an important feature for learning. Neural activity in the cortical regions impacts myelination by regulating oligodendrocyte (OL) proliferation, differentiation, and myelin formation. We characterized newly formed oligodendrocyte progenitor cells, and mature OLs are reduced in TNP and are associated with reduced myelin strength in the ACC region. The functional disturbances in the BLA-ACC neural circuitry is pathologically associated with the myelin defects in the ACC region which may be relevant causes for the deficits in decision-making in chronic TNP state.

Astrocytic l-Lactate Signaling Facilitates Amygdala-Anterior Cingulate Cortex Synchrony and Decision Making in Rats.

Human brain imaging studies have revealed the anterior cingulate cortex (ACC) as a key brain region for mediating visceral-pain-cognitive interactions. Recently, we characterized impairments of long-term potentiation and spike-field coherence in the basolateral amygdala (BLA)-ACC network in association with a decision-making deficit in rats with visceral hypersensitivity (VH). Now, by combining integrative neurobiological approaches, we show that ACC-reactive astrogliosis and activity-dependent impairment of lactate release occur in VH rats. Exogenous lactate supply rescues chronic-visceral-pain-caused impairments of ACC phase locking and decision making, which can be mimicked by optogenetic activation of ACC astrocytes. Large-scale electrophysiological recordings in free-moving animals during a decision-making task indicate that optogenetic astrocytic activation improves decision-making performance and engages ACC phase locking and BLA-to-ACC information flow. Collectively, these observations support the idea of an "astrocyte-neuron l-lactate shuttle" and suggest that targeting astrocytes may help with cognitive dysfunctions under chronic visceral pain.