A novel conditional genetic system reveals that increasing neuronal cAMP enhances memory and retrieval.

Consistent evidence from pharmacological and genetic studies shows that cAMP is a critical modulator of synaptic plasticity and memory formation. However, the potential of the cAMP signaling pathway as a target for memory enhancement remains unclear because of contradictory findings from pharmacological and genetic approaches. To address these issues, we have developed a novel conditional genetic system in mice based on the heterologous expression of an Aplysia octopamine receptor, a G-protein-coupled receptor whose activation by its natural ligand octopamine leads to rapid and transient increases in cAMP. We find that activation of this receptor transgenically expressed in mouse forebrain neurons induces a rapid elevation of hippocampal cAMP levels, facilitates hippocampus synaptic plasticity, and enhances the consolidation and retrieval of fear memory. Our findings clearly demonstrate that acute increases in cAMP levels selectively in neurons facilitate synaptic plasticity and memory, and illustrate the potential of this heterologous system to study cAMP-mediated processes in mammalian systems.

Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB:CBP-dependent transcriptional activation.

Histone deacetylase (HDAC) inhibitors increase histone acetylation and enhance both memory and synaptic plasticity. The current model for the action of HDAC inhibitors assumes that they alter gene expression globally and thus affect memory processes in a nonspecific manner. Here, we show that the enhancement of hippocampus-dependent memory and hippocampal synaptic plasticity by HDAC inhibitors is mediated by the transcription factor cAMP response element-binding protein (CREB) and the recruitment of the transcriptional coactivator and histone acetyltransferase CREB-binding protein (CBP) via the CREB-binding domain of CBP. Furthermore, we show that the HDAC inhibitor trichostatin A does not globally alter gene expression but instead increases the expression of specific genes during memory consolidation. Our results suggest that HDAC inhibitors enhance memory processes by the activation of key genes regulated by the CREB:CBP transcriptional complex.

Impact of overbite and overjet on oral health-related quality of life of children and adolescents.

BACKGROUND: Usually, morphological parameters of the teeth are recorded to help assess the indication for orthodontic treatment. It is assumed that significant deviations from average values compromise the quality of life. The aim of this study is to analyse the impact of overbite and overjet on oral health-related quality of life (OHRQoL) of children and adolescents. PATIENTS AND METHODS: A total of 748 subjects, aged 9.5-15.5 years, participated in the LIFE child project of the University of Leipzig, where they underwent a general medical and dental examination. Overbite and overjet were measured, and aberrations of the OHRQoL were recorded by the probands themselves, who completed the German version of the Child Perceptions Questionnaire (CPQ-G11-14). The OHRQoL is divided into four domains ("oral symptoms", "functional limitations", "emotional well-being" and "social well-being") and is analysed by means of a CPQ score depending on age, gender, socioeconomic status and orthodontic treatment. RESULTS: On average, the participants listed 10.5 (±13.1) problem issues on a CPQ scale ranging from 0 to 140. Subjects with current orthodontic treatment had a CPQ score about 2.5 (±2.4) higher than those without treatment. The aberrations were mainly observed in the domains "oral symptoms" and "functional limitations". Multiple linear regression showed that deviations of the overbite had only little influence on the OHRQoL, but deviations of an overjet-especially of >6 mm increased the CPQ summary score about 6 points. CONCLUSION: Children and adolescents with overjet deviations of >6 mm in comparison to the norm are associated with significant limitations of the OHRQoL. However, overbite deviations have only little influence.

Constitutive activation of Galphas within forebrain neurons causes deficits in sensorimotor gating because of PKA-dependent decreases in cAMP.

Sensorimotor gating, the ability to automatically filter sensory information, is deficient in a number of psychiatric disorders, yet little is known of the biochemical mechanisms underlying this critical neural process. Previously, we reported that mice expressing a constitutively active isoform of the G-protein subunit Galphas (Galphas(*)) within forebrain neurons exhibit decreased gating, as measured by prepulse inhibition of acoustic startle (PPI). Here, to elucidate the biochemistry regulating sensorimotor gating and to identify novel therapeutic targets, we test the hypothesis that Galphas(*) causes PPI deficits via brain region-specific changes in cyclic AMP (cAMP) signaling. As predicted from its ability to stimulate adenylyl cyclase, we find here that Galphas(*) increases cAMP levels in the striatum. Suprisingly, however, Galphas(*) mice exhibit reduced cAMP levels in the cortex and hippocampus because of increased cAMP phosphodiesterase (cPDE) activity. It is this decrease in cAMP that appears to mediate the effect of Galphas(*) on PPI because Rp-cAMPS decreases PPI in C57BL/6J mice. Furthermore, the antipsychotic haloperidol increases both PPI and cAMP levels specifically in Galphas(*) mice and the cPDE inhibitor rolipram also rescues PPI deficits of Galphas(*) mice. Finally, to block potentially the pathway that leads to cPDE upregulation in Galphas(*) mice, we coexpressed the R(AB) transgene (a dominant-negative regulatory subunit of protein kinase A (PKA)), which fully rescues the reductions in PPI and cAMP caused by Galphas(*). We conclude that expression of Galphas(*) within forebrain neurons causes PPI deficits because of a PKA-dependent decrease in cAMP and suggest that cAMP PDE inhibitors may exhibit antipsychotic-like therapeutic effects.

Viewing facial expressions of pain engages cortical areas involved in the direct experience of pain.

Recent neuroimaging and neuropsychological work has begun to shed light on how the brain responds to the viewing of facial expressions of emotion. However, one important category of facial expression that has not been studied on this level is the facial expression of pain. We investigated the neural response to pain expressions by performing functional magnetic resonance imaging (fMRI) as subjects viewed short video sequences showing faces expressing either moderate pain or, for comparison, no pain. In alternate blocks, the same subjects received both painful and non-painful thermal stimulation. Facial expressions of pain were found to engage cortical areas also engaged by the first-hand experience of pain, including anterior cingulate cortex and insula. The reported findings corroborate other work in which the neural response to witnessed pain has been examined from other perspectives. In addition, they lend support to the idea that common neural substrates are involved in representing one's own and others' affective states.

The role of prefrontal cortex in resolving distractor interference.

We investigate the hypothesis that those subregions of the prefrontal cortex (PFC) found to support proactive interference resolution may also support delay-spanning distractor interference resolution. Ten subjects performed delayed-recognition tasks requiring working memory for faces or shoes during functional MRI scanning. During the 15-sec delay interval, task-irrelevant distractors were presented. These distractors were either all faces or all shoes and were thus either congruent or incongruent with the domain of items in the working memory task. Delayed-recognition performance was slower and less accurate during congruent than during incongruent trials. Our fMRI analyses revealed significant delay interval activity for face and shoe working memory tasks within both dorsal and ventral PFC. However, only ventral PFC activity was modulated by distractor category, with greater activity for congruent than for incongruent trials. Importantly, this congruency effect was only present for correct trials. In addition to PFC, activity within the fusiform face area was investigated. During face distraction, activity was greater for face relative to shoe working memory. As in ventrolateral PFC, this congruency effect was only present for correct trials. These results suggest that the ventrolateral PFC and fusiform face area may work together to support delay-spanning interference resolution.