Pain in the Brain: One of the major challenges in pain research is finding ways to reverse chronic pain. Synaptic long-term potentiation (LTP) at spinal or cortical levels is a cellular model of chronic pain. X.-Y. Li. et al. (p. 1400 ) studied the role of the enzyme protein kinase M zeta (PKMζ) in neurons of the anterior cingulate cortex (ACC) in the maintenance of LTP and for enhanced pain sensitivity after peripheral nerve injury in mice. Nerve injury appeared to lead to the up-regulation and phosphorylation of PKMζ. This triggered LTP at some synapses in the ACC by increasing the number of AMPA receptors. LTP was restricted to ACC neurons that were activated by nerve injury. Blocking PKMζ in the ACC days after nerve injury normalized pain behavior. Thus, PKMζ may represent a promising target for the treatment of chronic pain.

It is well known that sleep deprivation can have cognitive consequences, including learning and memory deficits, but the mechanisms by which sleep deprivation affects brain function remain unknown. New experiments identify the cyclic AMP pathway as a functional target of sleep deprivation, specifically the impairment of cAMP/PKA-based plasticity in the hippocampus. Rescuing cAMP signalling using phosphodiesterase inhibitors also rescues the memory deficits, pointing to cAMP/PKA signalling enhancers as a possible therapeutic approach to counteract the cognitive effects of lost sleep. Sleep deprivation can have adverse cognitive effects, with one of the major consequences on the brain being memory deficits in learning models that are dependent on the hippocampus. A molecular mechanism by which brief sleep deprivation alters hippocampal function is now identified in mice; it involves the impairment of cyclic-AMP- and protein-kinase-A-dependent forms of synaptic plasticity. Millions of people regularly obtain insufficient sleep1. Given the effect of sleep deprivation on our lives, understanding the cellular and molecular pathways affected by sleep deprivation is clearly of social and clinical importance. One of the major effects of sleep deprivation on the brain is to produce memory deficits in learning models that are dependent on the hippocampus2,3,4,5. Here we have identified a molecular mechanism by which brief sleep deprivation alters hippocampal function. Sleep deprivation selectively impaired 3′, 5′-cyclic AMP (cAMP)- and protein kinase A (PKA)-dependent forms of synaptic plasticity6 in the mouse hippocampus, reduced cAMP signalling, and increased activity and protein levels of phosphodiesterase 4 (PDE4), an enzyme that degrades cAMP. Treatment of mice with phosphodiesterase inhibitors rescued the sleep-deprivation-induced deficits in cAMP signalling, synaptic plasticity and hippocampus-dependent memory. These findings demonstrate that brief sleep deprivation disrupts hippocampal function by interfering with cAMP signalling through increased PDE4 activity. Thus, drugs that enhance cAMP signalling may provide a new therapeutic approach to counteract the cognitive effects of sleep deprivation.

The lateral parabrachial nucleus (LPBN) is known to relay noxious information to the amygdala for processing affective responses. However, it is unclear whether the LPBN actively processes neuropathic pain characterized by persistent hyperalgesia with aversive emotional responses. Here we report that neuropathic pain-like hypersensitivity induced by common peroneal nerve (CPN) ligation increases nociceptive stimulation-induced responses in glutamatergic LPBN neurons. Optogenetic activation of GABAergic LPBN neurons does not affect basal nociception, but alleviates neuropathic pain-like behavior. Optogenetic activation of glutamatergic or inhibition of GABAergic LPBN neurons induces neuropathic pain-like behavior in naïve mice. Inhibition of glutamatergic LPBN neurons alleviates both basal nociception and neuropathic pain-like hypersensitivity. Repetitive pharmacogenetic activation of glutamatergic or GABAergic LPBN neurons respectively mimics or prevents the development of CPN ligation-induced neuropathic pain-like hypersensitivity. These findings indicate that a delicate balance between excitatory and inhibitory LPBN neuronal activity governs the development and maintenance of neuropathic pain.

NG2 cells originate from various brain regions and migrate to their destinations during early development. These cells express voltage-gated Na⁺ channels but fail to produce typical action potentials. The physiological role of Na⁺ channels in these cells is unclear. We found that GABA induces membrane depolarization and Ca²⁺ elevation in NG2 cells, a process requiring activation of GABA_A receptors, Na⁺ channels, and Na⁺/Ca²⁺ exchangers (NCXs), but not Ca²⁺ channels. We have identified a persistent Na⁺ current in these cells that may underlie the GABA-induced pathway of prolonged Na⁺ elevation, which in turn triggers Ca²⁺ influx via NCXs. This unique Ca²⁺ signaling pathway is further shown to be involved in the migration of NG2 cells. Thus, GABAergic signaling mediated by sequential activation of GABA_A receptors, noninactivating Na⁺ channels, and NCXs may play an important role in the development and function of NG2 glial cells in the brain.