Electrophysiological properties of basal forebrain cholinergic neurons identified by genetic and optogenetic tagging.

Recent developments in the generation of neuronal population-specific, genetically modified mouse lines have allowed precise identification and selective stimulation of cholinergic neurons in vivo. Although considerably less laborious than studies conducted with post hoc identification of cholinergic neurons by immunostaining, it is not known whether the genetically based labeling procedures that permit in vivo identification are electrophysiologically benign. In this study, we use mice carrying a bacterial artificial chromosome transgene that drives expression of a tau-green fluorescent fusion protein specifically in cholinergic neurons. This allowed us to visualize basal forebrain cholinergic neurons in acute slice preparations. Using whole cell, patch clamp electrophysiological recording in acute brain slices, here we present original data about the basic electrical properties of these genetically tagged cholinergic neurons including firing rate, resting membrane potential, rheobase, and various characteristics of their action potentials and after-hyperpolarization potentials. The basic electrical properties are compared (i) with non-cholinergic neurons in the same brain regions; (ii) in cholinergic neurons between immature animals and young adults; and (iii) with cholinergic neurons that are expressing light-sensitive channels. Our conclusions based on these data are (i) cholinergic neurons are less excitable then their non-cholinergic neighbors, (ii) the basic properties of cholinergic neurons do not significantly change between adolescence and young adulthood and (iii) these properties are not significantly affected by chronic expression of the excitatory opsin, oChIEF. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms.

Resounding attachment: cancer inpatients' song lyrics for their children in music therapy.

GOALS OF WORK: Scant attention focuses on supporting parent-child communication during the parents' cancer hospitalizations. Parents may struggle to remain emotionally available. Caregiver absences may threaten secure attachment relationships with infants and elicit problems amongst older children. Music therapists help many parents with cancer to compose songs for their children. Their lyric analysis may provide insight into song writing's communicative and therapeutic potential. MATERIALS AND METHODS: Two song lyric groups were comparatively analyzed (based on grounded theory). One group included 19 songs written by 12 patients with the first author. Another included 16 songs written by 15 patients with three music therapists (including two authors), which were previously published or recorded for the public. Songs were composed by 20 mothers and seven fathers for at least 46 offspring. All parents had hematological or metastatic diseases. Qualitative inter-rater reliability was integrated. MAIN RESULTS: Comparable lyrical ideas in the two parent song groups included: love; memories; yearning for children; metaphysical presence (now and afterlife); loss and grief; the meaning and helpfulness of the children in their lives; hopes for and compliments about their children; encouragement; requests; personal reflections; existential beliefs; and suggestions about to whom the children can turn. CONCLUSIONS: Parents' song lyric messages may support their children during the parents' illnesses and through the children's developmental transitions and possible bereavement. Some parents use song writing for catharsis and to encourage their children's continuing attachment with them after death. Through promoting parent-child connectedness and emotional expression, therapeutic song writing can be a valuable oncologic supportive care modality.

Mecp2 Deletion from Cholinergic Neurons Selectively Impairs Recognition Memory and Disrupts Cholinergic Modulation of the Perirhinal Cortex.

Rett Syndrome is a neurological disorder caused by mutations in the gene encoding methyl CpG binding protein 2 (MeCP2) and characterized by severe intellectual disability. The cholinergic system is a critical modulator of cognitive ability and is affected in patients with Rett Syndrome. To better understand the importance of MeCP2 function in cholinergic neurons, we studied the effect of selective Mecp2 deletion from cholinergic neurons in mice. Mice with Mecp2 deletion from cholinergic neurons were selectively impaired in assays of recognition memory, a cognitive task largely mediated by the perirhinal cortex (PRH). Deletion of Mecp2 from cholinergic neurons resulted in profound alterations in baseline firing of L5/6 neurons and eliminated the responses of these neurons to optogenetic stimulation of cholinergic input to PRH. Both the behavioral and the electrophysiological deficits of cholinergic Mecp2 deletion were rescued by inhibiting ACh breakdown with donepezil treatment.

Basal Forebrain Cholinergic Circuits and Signaling in Cognition and Cognitive Decline.

Recent work continues to place cholinergic circuits at center stage for normal executive and mnemonic functioning and provides compelling evidence that the loss of cholinergic signaling and cognitive decline are inextricably linked. This Review focuses on the last few years of studies on the mechanisms by which cholinergic signaling contributes to circuit activity related to cognition. We attempt to identify areas of controversy, as well as consensus, on what is and is not yet known about how cholinergic signaling in the CNS contributes to normal cognitive processes. In addition, we delineate the findings from recent work on the extent to which dysfunction of cholinergic circuits contributes to cognitive decline associated with neurodegenerative disorders.

Cholinergic Signaling Controls Conditioned Fear Behaviors and Enhances Plasticity of Cortical-Amygdala Circuits.

We examined the contribution of endogenous cholinergic signaling to the acquisition and extinction of fear- related memory by optogenetic regulation of cholinergic input to the basal lateral amygdala (BLA). Stimulation of cholinergic terminal fields within the BLA in awake-behaving mice during training in a cued fear-conditioning paradigm slowed the extinction of learned fear as assayed by multi-day retention of extinction learning. Inhibition of cholinergic activity during training reduced the acquisition of learned fear behaviors. Circuit mechanisms underlying the behavioral effects of cholinergic signaling in the BLA were assessed by in vivo and ex vivo electrophysiological recording. Photostimulation of endogenous cholinergic input (1) enhances firing of putative BLA principal neurons through activation of acetylcholine receptors (AChRs), (2) enhances glutamatergic synaptic transmission in the BLA, and (3) induces LTP of cortical-amygdala circuits. These studies support an essential role of cholinergic modulation of BLA circuits in the inscription and retention of fear memories.

Emotion potentiated startle in fragile X syndrome.

Social avoidance and anxiety are prevalent in fragile X syndrome (FXS) and are potentially mediated by the amygdala, a brain region critical for social behavior. Unfortunately, functional brain resonance imaging investigation of the amygdala in FXS is limited by the difficulties experienced by intellectually impaired and anxious participants. We investigated the relationship between social avoidance and emotion-potentiated startle, a probe of amygdala activation, in children and adolescents with FXS, developmental disability without FXS (DD), and typical development. Individuals with FXS or DD demonstrated significantly reduced potentiation to fearful faces than a typically developing control group (p < .05). However, among individuals with FXS, social avoidance correlated positively with fearful-face potentiation (p < .05). This suggests that general intellectual disability blunts amygdalar response, but differential amygdala responsiveness to social stimuli contributes to phenotypic variability among individuals with FXS.

Prepulse inhibition in patients with fragile X-associated tremor ataxia syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset neurodegenerative disorder that affects carriers of the fragile X premutation, typically after age 50. Common symptoms include intention tremor, ataxia, neuropathy, autonomic dysfunction, cognitive decline, and dementia. The objectives of this study were to determine if patients with FXTAS have altered prepulse inhibition (PPI; a measure of sensorimotor gating), and to study possible correlations between PPI, molecular status, and cognitive performance. A passive acoustic PPI paradigm was applied in 163 subjects; 121 carriers of the fragile X premutation, and 42 healthy controls. There were significant differences in PPI between premutation carriers with FXTAS and controls at PPI 60 ms, and at 120 ms. This effect was more prominent in the male FXTAS patients. There was a tendency to an impaired PPI in female premutation carriers at the 120 ms condition. There was a significant correlation between the PPI deficit and a higher CGG repeat number. The results show an impairment in sensorimotor gating processes in male carriers of the fragile X premutation, which is more prominent in patients with FXTAS.

Clinical assessment of DSM-IV anxiety disorders in fragile X syndrome: prevalence and characterization.

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability (ID). Anxiety and social withdrawal are considered core features of the FXS phenotype, yet there is limited diagnostic evidence of the prevalence of formal anxiety disorders in FXS. This study assessed the prevalence of anxiety disorders in a sample of 58 males and 39 females with FXS (ages 5.0-33.3 years). Participants' parents completed the Anxiety Disorders Interview Schedule (ADIS-IV), a clinical interview based on DSM-IV criteria, and the Anxiety Depression and Mood Scale (ADAMS), a psychiatric disorders screening instrument normed in ID. We conducted cognitive (IQ) and autism (AUT) assessments and surveyed medication use. Despite a high rate of psychopharmacological treatment, 86.2% of males and 76.9% of females met criteria for an anxiety disorder, with social phobia and specific phobia the most commonly diagnosed. Proband status, gender, and IQ were not significantly related to any anxiety disorders, however significantly higher rates of a few anxiety disorders were found in older age and AUT groups. Significant correlations between ADIS diagnoses and ADAMS scores provided cross-validation of instruments, indicating that the ADIS is suitable for use in FXS. A greater percentage of our sample met criteria for most anxiety disorders than has been reported in other ID groups or the general population. The rate of anxiety compared to general ID suggests that the FMR1 full mutation confers an especially high risk for these disorders, regardless of factors commonly associated with FXS clinical involvement. A thorough clinical assessment and treatment of anxiety should be included in the FXS standard of care.

Brief report: Sensorimotor gating in idiopathic autism and autism associated with fragile X syndrome.

Prepulse inhibition (PPI) may useful for exploring the proposed shared neurobiology between idiopathic autism and autism caused by FXS. We compared PPI in four groups: typically developing controls (n = 18), FXS and autism (FXS+A; n = 15), FXS without autism spectrum disorder (FXS-A; n = 17), and idiopathic autism (IA; n = 15). Relative to controls, the FXS+A (p < 0.002) and FXS-A (p < 0.003) groups had impaired PPI. The FXS+A (p < 0.01) and FXS-A (p < 0.03) groups had lower PPI than the IA group. Prolonged startle latency was seen in the IA group. The differing PPI profiles seen in the FXS+A and IA indicates these groups may not share a common neurobiological abnormality of sensorimotor gating.