Exposures to uncontrollable stress have been shown to alter ensuing synaptic plasticity in the hippocampus and interfere with hippocampal-dependent spatial memory in rats. The present study examined whether stress, which impairs hippocampal long-term potentiation (LTP), also affects (nonspatial) hippocampal-dependent object-recognition memory, as tested on the visual paired comparison task (VPC) in rats. After undergoing an inescapable restraint-tailshock stress experience, rats exhibited markedly impaired recognition memory at the 3-h (long) familiarization-to-test phase delay but not at the 5-min (short) delay. In contrast, unstressed control animals showed robust recognition memory (i.e., they exhibited reliable preferences for novel over familiar objects) at both short-and long-delay periods. The impairing effect of stress on long-delay recognition memory was transient because 48 h after undergoing stress experience, animals performed normally at the long delay. Similar to stress, microinfusions of DL-2-amino-5-phosphonovaleric acid (APV), a competitive N-methyl-D-aspartate receptor (NMDAR) antagonist that blocks LTP, into the dorsal hippocampus selectively impaired object-recognition memory at the long-delay period. Together, these results suggest that stress and intrahippocampal administration of APV affect recognition memory by influencing synaptic plasticity in the hippocampus.[The following individuals kindly provided reagents, samples, or unpublished information as indicated in the paper H. Blair.]

To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL). Based on these findings, potent, small-molecule inhibitors of AAK1 were identified. Studies in mice showed that one such inhibitor, LP-935509, caused a reduced pain response in phase II formalin and reversed fully established pain behavior following the SNL procedure. Further studies showed that the inhibitor also reduced evoked pain responses in the rat chronic constriction injury (CCI) model and the rat streptozotocin model of diabetic peripheral neuropathy. Using a nonbrain-penetrant AAK1 inhibitor and local administration of an AAK1 inhibitor, the relevant pool of AAK1 for antineuropathic action was found to be in the spinal cord. Consistent with these results, AAK1 inhibitors dose-dependently reduced the increased spontaneous neural activity in the spinal cord caused by CCI and blocked the development of windup induced by repeated electrical stimulation of the paw. The mechanism of AAK1 antinociception was further investigated with inhibitors of α2 adrenergic and opioid receptors. These studies showed that α2 adrenergic receptor inhibitors, but not opioid receptor inhibitors, not only prevented AAK1 inhibitor antineuropathic action in behavioral assays, but also blocked the AAK1 inhibitor–induced reduction in spinal neural activity in the rat CCI model. Hence, AAK1 inhibitors are a novel therapeutic approach to neuropathic pain with activity in animal models that is mechanistically linked (behaviorally and electrophysiologically) to α2 adrenergic signaling, a pathway known to be antinociceptive in humans.

Impaired spatial learning is a prominent deficit in fragile X syndrome (FXS). Previous studies using the Fmr1 knockout (KO) mouse model of FXS have not consistently reported a deficit in spatial learning. Fmr1 KO mice bred onto an albino C57BL/6J-Tyr c-Brd background showed significant deficits in several primary measures of performance during place navigation and probe trials in the Morris water maze. Fmr1 KO mice were also impaired during a serial reversal version of the water maze task. We examined fear conditioning as an additional cognitive screen. Knockout mice exhibited contextual memory deficits when trained with unsignaled shocks; however, deficits were not found in a separate group of KO mice trained with signaled shocks. No potentially confounding genotypic differences in locomotor activity were observed. A decreased anxiety-like profile was apparent in the open field, as others have noted, and also in the platform test. Also as previously reported, startle reactivity to loud auditory stimuli was decreased, prepulse inhibition and social interaction increased in KO mice. Female Fmr1 KO mice were tested along with male KO mice in all assays, except for social interaction. The female and male KO exhibited very similar impairments indicating that sex does not generally drive the behavioral symptoms of the disorder. Our results suggest that procedural factors, such as the use of albino mice, may help to reliably detect spatial learning and memory impairments in both sexes of Fmr1 KO mice, making it more useful for understanding FXS and a platform for evaluating potential therapeutics.

The relative contribution of left and right amygdalae in the acquisition and retention of fear conditioning was investigated in rats. Pretraining bilateral electrolytic lesions blocked the acquisition of conditioned fear to tone and context, whereas unilateral lesions induced partial impairments with no left-right amygdala differences. In contrast, posttraining bilateral and unilateral lesions produced significant deficits in the retention of conditioned fear to tone and context. Although no left-right difference was observed to tone, the right amygdala lesions generated greater deficits in contextual fear than the left amygdala lesions. These results indicate that fear conditioning is partially disrupted with unilateral amygdalar lesions, but that the right amygdala has greater involvement than the left amygdala when conditioning occurs under a normal brain state.

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