Spatial working memory (WM; i.e., "scratchpad" memory) is constantly updated to guide behavior based on representational knowledge of spatial position. It is maintained by spatially tuned, recurrent excitation within networks of prefrontal cortical (PFC) neurons, evident during delay periods in WM tasks. Stimulation of postsynaptic alpha2A adrenoceptors (alpha2A-ARs) is critical for WM. We report that alpha2A-AR stimulation strengthens WM through inhibition of cAMP, closing Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels and strengthening the functional connectivity of PFC networks. Ultrastructurally, HCN channels and alpha2A-ARs were colocalized in dendritic spines in PFC. In electrophysiological studies, either alpha2A-AR stimulation, cAMP inhibition or HCN channel blockade enhanced spatially tuned delay-related firing of PFC neurons. Conversely, delay-related network firing collapsed under conditions of excessive cAMP. In behavioral studies, either blockade or knockdown of HCN1 channels in PFC improved WM performance. These data reveal a powerful mechanism for rapidly altering the strength of WM networks in PFC.

Knowledge of how changes in bladder volume and the urge to void affect brain activity is important for understanding brain mechanisms that control urinary continence and micturition. This study used PET to evaluate brain activity associated with different levels of passive bladder filling and the urge to void. Eleven healthy male subjects (three left- and eight right-handed) aged 19-54 years were catheterized and the bladder filled retrogradely per urethra. Twelve PET scans were obtained during two repetitions of each of six bladder volumes, with the subjects rating their perception of urge to void prior to and after each scan. Increased brain activity related to increasing bladder volume was seen in the periaqueductal grey matter (PAG), in the midline pons, in the mid-cingulate cortex and bilaterally in the frontal lobe area. Increased brain activity relating to decreased urge to void was seen in a different portion of the cingulate cortex, in premotor cortex and in the hypothalamus. Both activation patterns were predominantly bilaterally symmetric and none of the effects could be attributed to the presence of the catheter. However, in some subjects, mostly those reporting intrusive sensations from the urethral catheter, there was a discrepancy between filling volume and urge so that they reported high urge with low volumes. As this 'mismatch' decreased, activation increased bilaterally in the somatosensory cortex. Our findings support the hypothesis that the PAG receives information about bladder fullness and relays this information to areas involved in the control of bladder storage. Our results also show that the network of brain regions involved in modulating the perception of the urge to void is distinct from that associated with the appreciation of bladder fullness.

Neuropsychological and imaging studies indicate that attention deficit hyperactivity disorder (ADHD) is associated with alterations in prefrontal cortex (PFC) and its connections to striatum and cerebellum. Research in animals, in combination with observations of patients with cortical lesions, has shown that the PFC is critical for the regulation of behavior, attention, and affect using representational knowledge. The PFC is important for sustaining attention over a delay, inhibiting distraction, and dividing attention, while more posterior cortical areas are essential for perception and the allocation of attentional resources. The PFC in the right hemisphere is especially important for behavioral inhibition. Lesions to the PFC produce a profile of distractibility, forgetfulness, impulsivity, poor planning, and locomotor hyperactivity. The PFC is very sensitive to its neurochemical environment, and either too little (drowsiness) or too much (stress) catecholamine release in PFC weakens cognitive control of behavior and attention. Recent electrophysiological studies in animals suggest that norepinephrine enhances "signals" through postsynaptic α2A adrenoceptors in PFC, while dopamine decreases "noise" through modest levels of D1 receptor stimulation. α2A-Adrenoceptor stimulation strengthens the functional connectivity of PFC networks, while blockade of α2 receptors in the monkey PFC recreates the symptoms of ADHD, resulting in impaired working memory, increased impulsivity, and locomotor hyperactivity. Genetic alterations in catecholamine pathways may contribute to dysregulation of PFC circuits in this disorder. Medications may have many of their therapeutic effects by optimizing stimulation of α2A adrenoceptors and D1 receptors in the PFC, thus strengthening PFC regulation of behavior and attention.

Purpose Central nervous system plasticity is essential for normal function, but can also reinforce abnormal network behavior, leading to epilepsy and other disorders. The role of altered ion channel expression in abnormal plasticity has not been thoroughly investigated. Nav1.6 is the most abundantly expressed sodium channel in the nervous system. Because of its distribution in the cell body and axon initial segment, Nav1.6 is crucial for action potential generation. The goal of the present study was to investigate the possible role of changes in Nav1.6 expression in abnormal, activity-dependent plasticity of hippocampal circuits. Methods We studied kindling, a form of abnormal activity-dependent facilitation. We investigated: 1. sodium channel protein expression by immunocytochemistry and sodium channel mRNA by in situ hybridization, 2. sodium current by patch clamp recordings, and 3. rate of kindling by analysis of seizure behavior. The initiation, development, and expression of kindling in wild type mice were compared to Nav1.6 +/− medtg mice, which have reduced expression of Nav1.6. Results We found that kindling was associated with increased expression of Nav1.6 protein and mRNA, which occurred selectively in hippocampal CA3 neurons. Hippocampal CA3 neurons also showed increased persistent sodium current in kindled animals compared to sham-kindled controls. Conversely, Nav1.6 +/− medtg mice resisted the initiation and development of kindling. Discussion These findings suggest an important mechanism for enhanced excitability, in which Nav1.6 may participate in a self-reinforcing cycle of activity-dependent facilitation in the hippocampus. This mechanism could contribute to both normal hippocampal function, and to epilepsy and other common nervous system disorders.

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BackgroundRestraint stress has been shown to elicit numerous effects on hippocampal function and neuronal morphology, as well as to induce dendritic remodeling in the prefrontal cortex (PFC). However, the effects of acute restraint stress on PFC cognitive function have not been investigated, despite substantial evidence that the PFC malfunctions in many stress-related disorders.MethodsThe present study examined the effects of restraint stress on PFC function in both male rats and cycling female rats in either the proestrus (high estrogen) or estrus (low estrogen) phase of the estrus cycle. Animals were restrained for 60 or 120 minutes and then tested on spatial delayed alternation, a PFC-mediated task. Performance after stress was compared to performance on a different day under no-stress conditions, and analyzed using analysis of variance (ANOVA).ResultsSixty minutes of restraint impaired only females in proestrus, while 120 minutes of restraint produced significant impairments in all animals. Increases in task completion times did not affect performance.ConclusionThese results demonstrate an interaction between hormonal status and cognitive response to stress in female rats, with high estrogen levels being associated with amplified sensitivity to stress. This effect has been previously observed after administration of a pharmacological stressor (the benzodiazepine inverse agonist FG7142), and results from both studies may be relevant to the increased prevalence of stress-related disorders, such as major depressive disorder, in cycling women. Overall, the results show that restraint stress has important effects on the cognitive functions of the PFC, and that hormonal influences in the PFC are an important area for future research.

Planning and directing thought and behavior require the working memory (WM) functions of prefrontal cortex. WM is compromised by stress, which activates phosphatidylinositol (PI)-mediated IP 3 -PKC intracellular signaling. PKC overactivation impairs WM operations and in vitro studies indicate that IP 3 receptor (IP 3 R)-evoked calcium release results in SK channel-dependent hyperpolarization of prefrontal neurons. However, the effects of IP 3 R signaling on prefrontal function have not been investigated. The present findings demonstrate that blockade of IP 3 R or SK channels in the prefrontal cortex enhances WM performance in rats, suggesting that both arms of the PI cascade influence prefrontal cognitive function.The prefrontal cortex coordinates and controls cognitive and emotional processes utilizing appropriate judgment, flexibility, and attention (Goldman-Rakic 1995a,b;Fuster 2000). A hallmark operation of the prefrontal cortex is working memory (WM)-the ability to internally maintain information in the absence of external representation. Debilitating deficits in WM and prefrontal function are associated with numerous conditions including schizophrenia, attention deficit hyperactivity disorder, aging, and stress (Goldman-Rakic 1992;Arnsten 1993;Goldman-Rakic and Selemon 1997;Ramos et al. 2003;Birnbaum et al. 2004). Elucidating mechanisms of cognitive impairment will contribute to identification and development of novel therapeutic targets for treatment of prefrontal decline.Local excitatory circuits are believed to underlie WM operations (Goldman-Rakic 1995a,b) and disruption in prefrontal neuronal activity is associated with WM impairment (GoldmanRakic 1995a,b). Disruptions can arise from altered catecholamine release within the prefrontal cortex. High levels of norepinephrine release, which typically follow a stressor (Rossetti et al. 1990;Finlay et al. 1995), impair WM performance by binding G qcoupled ␣1-adrenoceptors, leading to activation of the phosphatidylinositol (PI) cascade (Garcia-Sainz 1993;Birnbaum et al. 1999Birnbaum et al. , 2004. In the PI pathway, phospholipase C cleaves the phospholipid phosphatidylinositol bisphosphate (PIP 2 ) to generate membrane-bound diacylglycerol (DAG) and diffusible inositol 1, 4, 5-trisphosphate (IP 3 (Kohler et al. 1996). SK channels influence firing frequency by modulating after-hyperpolarization (Pedarzani et al. 2005;Sah 1996) and are therefore positioned to impact the network functions of the prefrontal cortex, which rely on highly synchronized sequences of firing. A recent study by Hagenston et al. (2007) indicates that IP 3 R-SK channel signaling regulates prefrontal neuron firing. IP 3 -mediated release of Ca 2+ resulted in hyperpolarization of layer V pyramidal neurons in rat medial prefrontal slices (Hagenston et al. 2007). This hyperpolarization was reversed by application of the SK channel blocker, apamin (Hagenston et al. 2007), suggesting a mechanistic role of SK channels in prefrontal dysfunction.This study sought to clarify whether IP 3 R sign...

Aging is associated with deficiencies in the prefrontal cortex, including working memory impairment, and compromised integrity of neuronal dendrites. Although protein kinase C (PKC) is implicated in structural plasticity, and overactivation of PKC results in working memory impairments in young animals, the role of PKC in prefrontal cortical impairments in the aged has not been examined. This study provides the first evidence that PKC activity is associated with prefrontal cortical dysfunction in aging. Pharmacological inhibition of PKC with chelerythrine rescued working memory impairments in aged rats and enhanced working memory in aged rhesus monkeys. Improvement correlated with age, with older monkeys demonstrating a greater degree of improvement following PKC inhibition. Furthermore, PKC activity within the prefrontal cortex was inversely correlated with the length of basal dendrites of prefrontal cortical neurons, as well as with working memory performance in aged rats. Together these findings indicate that PKC is dysregulated in aged animals and that PKC inhibitors may be useful in the treatment of cognitive deficits in the elderly.