A kinesin motor in a force-producing conformation.

BACKGROUND: Kinesin motors hydrolyze ATP to produce force and move along microtubules, converting chemical energy into work by a mechanism that is only poorly understood. Key transitions and intermediate states in the process are still structurally uncharacterized, and remain outstanding questions in the field. Perturbing the motor by introducing point mutations could stabilize transitional or unstable states, providing critical information about these rarer states. RESULTS: Here we show that mutation of a single residue in the kinesin-14 Ncd causes the motor to release ADP and hydrolyze ATP faster than wild type, but move more slowly along microtubules in gliding assays, uncoupling nucleotide hydrolysis from force generation. A crystal structure of the motor shows a large rotation of the stalk, a conformation representing a force-producing stroke of Ncd. Three C-terminal residues of Ncd, visible for the first time, interact with the central beta-sheet and dock onto the motor core, forming a structure resembling the kinesin-1 neck linker, which has been proposed to be the primary force-generating mechanical element of kinesin-1. CONCLUSIONS: Force generation by minus-end Ncd involves docking of the C-terminus, which forms a structure resembling the kinesin-1 neck linker. The mechanism by which the plus- and minus-end motors produce force to move to opposite ends of the microtubule appears to involve the same conformational changes, but distinct structural linkers. Unstable ADP binding may destabilize the motor-ADP state, triggering Ncd stalk rotation and C-terminus docking, producing a working stroke of the motor.

Altered ultrasonic vocalization and impaired learning and memory in Angelman syndrome mouse model with a large maternal deletion from Ube3a to Gabrb3.

Angelman syndrome (AS) is a neurobehavioral disorder associated with mental retardation, absence of language development, characteristic electroencephalography (EEG) abnormalities and epilepsy, happy disposition, movement or balance disorders, and autistic behaviors. The molecular defects underlying AS are heterogeneous, including large maternal deletions of chromosome 15q11-q13 (70%), paternal uniparental disomy (UPD) of chromosome 15 (5%), imprinting mutations (rare), and mutations in the E6-AP ubiquitin ligase gene UBE3A (15%). Although patients with UBE3A mutations have a wide spectrum of neurological phenotypes, their features are usually milder than AS patients with deletions of 15q11-q13. Using a chromosomal engineering strategy, we generated mutant mice with a 1.6-Mb chromosomal deletion from Ube3a to Gabrb3, which inactivated the Ube3a and Gabrb3 genes and deleted the Atp10a gene. Homozygous deletion mutant mice died in the perinatal period due to a cleft palate resulting from the null mutation in Gabrb3 gene. Mice with a maternal deletion (m-/p+) were viable and did not have any obvious developmental defects. Expression analysis of the maternal and paternal deletion mice confirmed that the Ube3a gene is maternally expressed in brain, and showed that the Atp10a and Gabrb3 genes are biallelically expressed in all brain sub-regions studied. Maternal (m-/p+), but not paternal (m+/p-), deletion mice had increased spontaneous seizure activity and abnormal EEG. Extensive behavioral analyses revealed significant impairment in motor function, learning and memory tasks, and anxiety-related measures assayed in the light-dark box in maternal deletion but not paternal deletion mice. Ultrasonic vocalization (USV) recording in newborns revealed that maternal deletion pups emitted significantly more USVs than wild-type littermates. The increased USV in maternal deletion mice suggests abnormal signaling behavior between mothers and pups that may reflect abnormal communication behaviors in human AS patients. Thus, mutant mice with a maternal deletion from Ube3a to Gabrb3 provide an AS mouse model that is molecularly more similar to the contiguous gene deletion form of AS in humans than mice with Ube3a mutation alone. These mice will be valuable for future comparative studies to mice with maternal deficiency of Ube3a alone.

Association between attention-deficit/hyperactivity disorder symptoms and obesity and hypertension in early adulthood: a population-based study.

OBJECTIVE: To examine the associations between attention-deficit/hyperactivity disorder (ADHD) symptoms, obesity and hypertension in young adults in a large population-based cohort. DESIGN, SETTING AND PARTICIPANTS: The study population consisted of 15,197 respondents from the National Longitudinal Study of Adolescent Health, a nationally representative sample of adolescents followed from 1995 to 2009 in the United States. Multinomial logistic and logistic models examined the odds of overweight, obesity and hypertension in adulthood in relation to retrospectively reported ADHD symptoms. Latent curve modeling was used to assess the association between symptoms and naturally occurring changes in body mass index (BMI) from adolescence to adulthood. RESULTS: Linear association was identified between the number of inattentive (IN) and hyperactive/impulsive (HI) symptoms and waist circumference, BMI, diastolic blood pressure and systolic blood pressure (all P-values for trend <0.05). Controlling for demographic variables, physical activity, alcohol use, smoking and depressive symptoms, those with three or more HI or IN symptoms had the highest odds of obesity (HI 3+, odds ratio (OR)=1.50, 95% confidence interval (CI) = 1.22-2.83; IN 3+, OR = 1.21, 95% CI = 1.02-1.44) compared with those with no HI or IN symptoms. HI symptoms at the 3+ level were significantly associated with a higher OR of hypertension (HI 3+, OR = 1.24, 95% CI = 1.01-1.51; HI continuous, OR = 1.04, 95% CI = 1.00-1.09), but associations were nonsignificant when models were adjusted for BMI. Latent growth modeling results indicated that compared with those reporting no HI or IN symptoms, those reporting 3 or more symptoms had higher initial levels of BMI during adolescence. Only HI symptoms were associated with change in BMI. CONCLUSION: Self-reported ADHD symptoms were associated with adult BMI and change in BMI from adolescence to adulthood, providing further evidence of a link between ADHD symptoms and obesity.

Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway.

PURPOSE: The endoplasmic reticulum-associated degradation pathway is responsible for the translocation of misfolded proteins across the endoplasmic reticulum membrane into the cytosol for subsequent degradation by the proteasome. To define the phenotype associated with a novel inherited disorder of cytosolic endoplasmic reticulum-associated degradation pathway dysfunction, we studied a series of eight patients with deficiency of N-glycanase 1. METHODS: Whole-genome, whole-exome, or standard Sanger sequencing techniques were employed. Retrospective chart reviews were performed in order to obtain clinical data. RESULTS: All patients had global developmental delay, a movement disorder, and hypotonia. Other common findings included hypolacrima or alacrima (7/8), elevated liver transaminases (6/7), microcephaly (6/8), diminished reflexes (6/8), hepatocyte cytoplasmic storage material or vacuolization (5/6), and seizures (4/8). The nonsense mutation c.1201A>T (p.R401X) was the most common deleterious allele. CONCLUSION: NGLY1 deficiency is a novel autosomal recessive disorder of the endoplasmic reticulum-associated degradation pathway associated with neurological dysfunction, abnormal tear production, and liver disease. The majority of patients detected to date carry a specific nonsense mutation that appears to be associated with severe disease. The phenotypic spectrum is likely to enlarge as cases with a broader range of mutations are detected.

Molecular mapping of movement-associated areas in the avian brain: a motor theory for vocal learning origin.

Vocal learning is a critical behavioral substrate for spoken human language. It is a rare trait found in three distantly related groups of birds-songbirds, hummingbirds, and parrots. These avian groups have remarkably similar systems of cerebral vocal nuclei for the control of learned vocalizations that are not found in their more closely related vocal non-learning relatives. These findings led to the hypothesis that brain pathways for vocal learning in different groups evolved independently from a common ancestor but under pre-existing constraints. Here, we suggest one constraint, a pre-existing system for movement control. Using behavioral molecular mapping, we discovered that in songbirds, parrots, and hummingbirds, all cerebral vocal learning nuclei are adjacent to discrete brain areas active during limb and body movements. Similar to the relationships between vocal nuclei activation and singing, activation in the adjacent areas correlated with the amount of movement performed and was independent of auditory and visual input. These same movement-associated brain areas were also present in female songbirds that do not learn vocalizations and have atrophied cerebral vocal nuclei, and in ring doves that are vocal non-learners and do not have cerebral vocal nuclei. A compilation of previous neural tracing experiments in songbirds suggests that the movement-associated areas are connected in a network that is in parallel with the adjacent vocal learning system. This study is the first global mapping that we are aware for movement-associated areas of the avian cerebrum and it indicates that brain systems that control vocal learning in distantly related birds are directly adjacent to brain systems involved in movement control. Based upon these findings, we propose a motor theory for the origin of vocal learning, this being that the brain areas specialized for vocal learning in vocal learners evolved as a specialization of a pre-existing motor pathway that controls movement.

Specialized motor-driven dusp1 expression in the song systems of multiple lineages of vocal learning birds.

Mechanisms for the evolution of convergent behavioral traits are largely unknown. Vocal learning is one such trait that evolved multiple times and is necessary in humans for the acquisition of spoken language. Among birds, vocal learning is evolved in songbirds, parrots, and hummingbirds. Each time similar forebrain song nuclei specialized for vocal learning and production have evolved. This finding led to the hypothesis that the behavioral and neuroanatomical convergences for vocal learning could be associated with molecular convergence. We previously found that the neural activity-induced gene dual specificity phosphatase 1 (dusp1) was up-regulated in non-vocal circuits, specifically in sensory-input neurons of the thalamus and telencephalon; however, dusp1 was not up-regulated in higher order sensory neurons or motor circuits. Here we show that song motor nuclei are an exception to this pattern. The song nuclei of species from all known vocal learning avian lineages showed motor-driven up-regulation of dusp1 expression induced by singing. There was no detectable motor-driven dusp1 expression throughout the rest of the forebrain after non-vocal motor performance. This pattern contrasts with expression of the commonly studied activity-induced gene egr1, which shows motor-driven expression in song nuclei induced by singing, but also motor-driven expression in adjacent brain regions after non-vocal motor behaviors. In the vocal non-learning avian species, we found no detectable vocalizing-driven dusp1 expression in the forebrain. These findings suggest that independent evolutions of neural systems for vocal learning were accompanied by selection for specialized motor-driven expression of the dusp1 gene in those circuits. This specialized expression of dusp1 could potentially lead to differential regulation of dusp1-modulated molecular cascades in vocal learning circuits.

The incidence of unacceptable movement with motor evoked potentials during craniotomy for aneurysm clipping.

OBJECTIVE: To review the experience at a single institution with motor evoked potential (MEP) monitoring during intracranial aneurysm surgery to determine the incidence of unacceptable movement. METHODS: Neurophysiology event logs and anesthetic records from 220 craniotomies for aneurysm clipping were reviewed for unacceptable patient movement or reason for cessation of MEPs. Muscle relaxants were not given after intubation. Transcranial MEPs were recorded from bilateral abductor hallucis and abductor pollicis muscles. MEP stimulus intensity was increased up to 500 V until evoked potential responses were detectable. RESULTS: Out of 220 patients, 7 (3.2%) exhibited unacceptable movement with MEP stimulation-2 had nociception-induced movement and 5 had excessive field movement. In all but one case, MEP monitoring could be resumed, yielding a 99.5% monitoring rate. CONCLUSIONS: With the anesthetic and monitoring regimen, the authors were able to record MEPs of the upper and lower extremities in all patients and found only 3.2% demonstrated unacceptable movement. With a suitable anesthetic technique, MEP monitoring in the upper and lower extremities appears to be feasible in most patients and should not be withheld because of concern for movement during neurovascular surgery.

Neural networks supporting autobiographical memory retrieval in posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) affects the functional recruitment and connectivity between neural regions during autobiographical memory (AM) retrieval that overlap with default and control networks. Whether such univariate changes relate to potential differences in the contributions of the large-scale neural networks supporting cognition in PTSD is unknown. In the present functional MRI study, we employed independent-component analysis to examine the influence of the engagement of neural networks during the recall of personal memories in a PTSD group (15 participants) as compared to non-trauma-exposed healthy controls (14 participants). We found that the PTSD group recruited similar neural networks when compared to the controls during AM recall, including default-network subsystems and control networks, but group differences emerged in the spatial and temporal characteristics of these networks. First, we found spatial differences in the contributions of the anterior and posterior midline across the networks, and of the amygdala in particular, for the medial temporal subsystem of the default network. Second, we found temporal differences within the medial prefrontal subsystem of the default network, with less temporal coupling of this network during AM retrieval in PTSD relative to controls. These findings suggest that the spatial and temporal characteristics of the default and control networks potentially differ in a PTSD group versus healthy controls and contribute to altered recall of personal memory.

Peace and war: trajectories of posttraumatic stress disorder symptoms before, during, and after military deployment in Afghanistan.

In the study reported here, we examined posttraumatic stress disorder (PTSD) symptoms in 746 Danish soldiers measured on five occasions before, during, and after deployment to Afghanistan. Using latent class growth analysis, we identified six trajectories of change in PTSD symptoms. Two resilient trajectories had low levels across all five times, and a new-onset trajectory started low and showed a marked increase of PTSD symptoms. Three temporary-benefit trajectories, not previously described in the literature, showed decreases in PTSD symptoms during (or immediately after) deployment, followed by increases after return from deployment. Predeployment emotional problems and predeployment traumas, especially childhood adversities, were predictors for inclusion in the nonresilient trajectories, whereas deployment-related stress was not. These findings challenge standard views of PTSD in two ways. First, they show that factors other than immediately preceding stressors are critical for PTSD development, with childhood adversities being central. Second, they demonstrate that the development of PTSD symptoms shows heterogeneity, which indicates the need for multiple measurements to understand PTSD and identify people in need of treatment.

Autobiographical memory for stressful events: the role of autobiographical memory in posttraumatic stress disorder.

To provide the three-way comparisons needed to test existing theories, we compared (1) most-stressful memories to other memories and (2) involuntary to voluntary memories (3) in 75 community dwelling adults with and 42 without a current diagnosis of posttraumatic stress disorder (PTSD). Each rated their three most-stressful, three most-positive, seven most-important and 15 word-cued autobiographical memories, and completed tests of personality and mood. Involuntary memories were then recorded and rated as they occurred for 2 weeks. Standard mechanisms of cognition and affect applied to extreme events accounted for the properties of stressful memories. Involuntary memories had greater emotional intensity than voluntary memories, but were not more frequently related to traumatic events. The emotional intensity, rehearsal, and centrality to the life story of both voluntary and involuntary memories, rather than incoherence of voluntary traumatic memories and enhanced availability of involuntary traumatic memories, were the properties of autobiographical memories associated with PTSD.

Functional neuroimaging of emotionally intense autobiographical memories in post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) affects regions that support autobiographical memory (AM) retrieval, such as the hippocampus, amygdala and ventral medial prefrontal cortex (PFC). However, it is not well understood how PTSD may impact the neural mechanisms of memory retrieval for the personal past. We used a generic cue method combined with parametric modulation analysis and functional MRI (fMRI) to investigate the neural mechanisms affected by PTSD symptoms during the retrieval of a large sample of emotionally intense AMs. There were three main results. First, the PTSD group showed greater recruitment of the amygdala/hippocampus during the construction of negative versus positive emotionally intense AMs, when compared to controls. Second, across both the construction and elaboration phases of retrieval the PTSD group showed greater recruitment of the ventral medial PFC for negatively intense memories, but less recruitment for positively intense memories. Third, the PTSD group showed greater functional coupling between the ventral medial PFC and the amygdala for negatively intense memories, but less coupling for positively intense memories. In sum, the fMRI data suggest that there was greater recruitment and coupling of emotional brain regions during the retrieval of negatively intense AMs in the PTSD group when compared to controls.

The coherence of memories for trauma: evidence from posttraumatic stress disorder.

Participants with posttraumatic stress disorder (PTSD) and participants with a trauma but without PTSD wrote narratives of their trauma and, for comparison, of the most-important and the happiest events that occurred within a year of their trauma. They then rated these three events on coherence. Based on participants' self-ratings and on naïve-observer scorings of the participants' narratives, memories of traumas were not more incoherent than the comparison memories in participants in general or in participants with PTSD. This study comprehensively assesses narrative coherence using a full two (PTSD or not) by two (traumatic event or not) design. The results are counter to most prevalent theoretical views of memory for trauma.

A memory-based model of posttraumatic stress disorder: evaluating basic assumptions underlying the PTSD diagnosis.

In the mnemonic model of posttraumatic stress disorder (PTSD), the current memory of a negative event, not the event itself, determines symptoms. The model is an alternative to the current event-based etiology of PTSD represented in the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; American Psychiatric Association, 2000). The model accounts for important and reliable findings that are often inconsistent with the current diagnostic view and that have been neglected by theoretical accounts of the disorder, including the following observations. The diagnosis needs objective information about the trauma and peritraumatic emotions but uses retrospective memory reports that can have substantial biases. Negative events and emotions that do not satisfy the current diagnostic criteria for a trauma can be followed by symptoms that would otherwise qualify for PTSD. Predisposing factors that affect the current memory have large effects on symptoms. The inability-to-recall-an-important-aspect-of-the-trauma symptom does not correlate with other symptoms. Loss or enhancement of the trauma memory affects PTSD symptoms in predictable ways. Special mechanisms that apply only to traumatic memories are not needed, increasing parsimony and the knowledge that can be applied to understanding PTSD.

Contrasting Models of Posttraumatic Stress Disorder: Reply to Monroe and Mineka (2008)

The authors address the 4 main points in S. M. Monroe and S. Mineka's (2008) comment. First, the authors show that the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; American Psychiatric Association, 2000) posttraumatic stress disorder (PTSD) diagnosis includes an etiology and that it is based on a theoretical model with a distinguished history in psychology and psychiatry. Two tenets of this theoretical model are that voluntary (strategic) recollections of the trauma are fragmented and incomplete while involuntary (spontaneous) recollections are vivid and persistent and yield privileged access to traumatic material. Second, the authors describe differences between their model and other cognitive models of PTSD. They argue that these other models share the same 2 tenets as the diagnosis and show that these 2 tenets are largely unsupported by empirical evidence. Third, the authors counter arguments about the strength of the evidence favoring the mnemonic model. Fourth, they show that concerns about the causal role of memory in PTSD are based on views of causality that are generally inappropriate for the explanation of PTSD in the social and biological sciences. © 2008 American Psychological Association.