Faculty Bibliography

Aberrant neuronal translation is implicated in the etiology of numerous brain disorders. Although mTORC1-p70 ribosomal S6 kinase 1 (S6K1) signaling is critical for translational control, pharmacological manipulation in vivo has targeted exclusively mTORC1 due to the paucity of specific inhibitors to S6K1.However, small molecule inhibitors of S6K1 could potentially ameliorate pathological phenotypes of diseases which are based on aberrant translation and protein expression. One such condition is Fragile X syndrome (FXS), which is considered to be caused by exaggerated neuronal translation and is the most frequent heritable cause of autism spectrum disorders (ASD). To date, potential therapeutic interventions in FXS have focused largely on targets upstream of translational control to normalize FXS-related phenotypes. Here we test the ability of two S6K1 inhibitors, PF-4708671 and FS-115, to normalize translational homeostasis and other phenotypes exhibited by FXS model mice. We found that although the pharmacokinetic profiles of the two S6K1 inhibitors differed, they overlapped in reversing multiple disease-associated phenotypes in FXS model mice including exaggerated protein synthesis, inappropriate social behavior, behavioral inflexibility, altered dendritic spine morphology, and macro-orchidism. In contrast, the two inhibitors differed in their ability to rescue stereotypic marble burying behavior and weight gain. These findings provide an initial pharmacological characterization of the impact of S6K1 inhibitors in vivo for FXS and have therapeutic implications for other neuropsychiatric conditions involving aberrant mTORC1-S6K1 signaling.Neuropsychopharmacology accepted article preview online, 28 December 2015. doi:10.1038/npp.2015.369.

This Opinion article considers the implications for functional anatomy of how we represent temporal structure in our exchanges with the world. It offers a theoretical treatment that tries to make sense of the architectural principles seen in mammalian brains. Specifically, it considers a factorisation between representations of temporal succession and representations of content or, heuristically, a segregation into when and what. This segregation may explain the central role of the hippocampus in neuronal hierarchies while providing a tentative explanation for recent observations of how ordinal sequences are encoded. The implications for neuroanatomy and physiology may have something important to say about how self-organised cell assembly sequences enable the brain to exhibit purposeful behaviour that transcends the here and now.

Diet, of course, influences urine chemistry. Yet only one randomized controlled trial has demonstrated that a change in diet led to reduction in stone recurrence. I will review some of the deficiencies in the current scientific dietary literature and suggest how these deficiencies could be addressed. Highlights will include comparisons of diet with pharmacologic therapy, how prescribing dietary patterns, rather than individual nutrients, might be a preferable way to address therapy, and the possible effect of the microbiome on how diet influences urinary chemistry

Alzheimer's disease (AD) age of onset (ADAOO) varies greatly between individuals, with unique causal mutations suggesting the role of modifying genetic and environmental interactions. We analyzed ~50 000 common and rare functional genomic variants from 71 individuals of the 'Paisa' pedigree, the world's largest pedigree segregating a severe form of early-onset AD, who were affected carriers of the fully penetrant E280A mutation in the presenilin-1 (PSEN1) gene. Affected carriers with ages at the extremes of the ADAOO distribution (30s-70s age range), and linear mixed-effects models were used to build single-locus regression models outlining the ADAOO. We identified the rs7412 (APOE*E2 allele) as a whole exome-wide ADAOO modifier that delays ADAOO by ~12 years (beta=11.74, 95% confidence interval (CI): 8.07-15.41, P=6.31 x 10-8, PFDR=2.48 x 10-3). Subsequently, to evaluate comprehensively the APOE (apolipoprotein E) haplotype variants (E1/E2/E3/E4), the markers rs7412 and rs429358 were genotyped in 93 AD affected carriers of the E280A mutation. We found that the APOE*E2 allele, and not APOE*E4, modifies ADAOO in carriers of the E280A mutation (beta=8.24, 95% CI: 4.45-12.01, P=3.84 x 10-5). Exploratory linear mixed-effects multilocus analysis suggested that other functional variants harbored in genes involved in cell proliferation, protein degradation, apoptotic and immune dysregulation processes (i.e., GPR20, TRIM22, FCRL5, AOAH, PINLYP, IFI16, RC3H1 and DFNA5) might interact with the APOE*E2 allele. Interestingly, suggestive evidence as an ADAOO modifier was found for one of these variants (GPR20) in a set of patients with sporadic AD from the Paisa genetic isolate. This is the first study demonstrating that the APOE*E2 allele modifies the natural history of AD typified by the age of onset in E280A mutation carriers. To the best of our knowledge, this is the largest analyzed sample of patients with a unique mutation sharing uniform environment. Formal replication of our results in other populations and in other forms of AD will be crucial for prediction, follow-up and presumably developing new therapeutic strategies for patients either at risk or affected by AD.Molecular Psychiatry advance online publication, 1 December 2015; doi:10.1038/mp.2015.177.

This symposium will review recent information regarding the relationship between diet and kidney stones. Information about diet and its effects on stone risk can be derived from 24 h urine collections. Recommendations regarding diet and beverage use will be surveyed. Proposals regarding randomized controlled trials, both past and future, will be presented

A major component of perception is hedonic valence: perceiving stimuli as pleasant or unpleasant. Here, we used early olfactory experiences that shape odor preferences and aversions to explore developmental plasticity in circuits mediating odor hedonics. We used 2-deoxyglucose autoradiographic mapping of neural activity to identify circuits differentially activated by biologically relevant preferred and avoided odors across rat development. We then further probed this system by increasing or decreasing hedonic value. Using both region of interest and functional connectivity analyses, we identified regions within primary olfactory, amygdala/hippocampal, and prefrontal cortical networks that were activated differentially by maternal and male odors. Although some activated regions remained stable across development (postnatal days 7-23), there was a developmental emergence of others that resulted in an age-dependent elaboration of hedonic-response-specific circuitry despite stable behavioral responses (approach/avoidance) to the odors across age. Hedonic responses to these biologically important odors were modified through diet suppression of the maternal odor and co-rearing with a male. This allowed assessment of hedonic circuits in isolation of the specific odor quality and/or intensity. Early experience significantly modified odor-evoked circuitry in an age-dependent manner. For example, co-rearing with a male, which induced pup attraction to male odor, reduced activity in amygdala regions normally activated by the unfamiliar avoided male odor, making this region more consistent with maternal odor. Understanding the development of odor hedonics, particularly within the context of altered early life experience, provides insight into the development of sensory processes, food preferences, and the formation of social affiliations, among other behaviors. SIGNIFICANCE STATEMENT: Odor hedonic valence controls approach-avoidance behaviors, but also modulates ongoing behaviors ranging from food preferences and social affiliation with the caregiver to avoidance of predator odors. Experiences can shape hedonic valence. This study explored brain circuitry involved in odor hedonic encoding throughout development using maternal and predator odors and assessed the effects of early life experience on odor hedonic encoding by increasing/decreasing the hedonic value of these odors. Understanding the role of changing brain circuitry during development and its impact on behavioral function is critical for understanding sensory processing across development. These data converge with exciting literature on the brain's hedonic network and highlight the significant role of early life experience in shaping the neural networks of highly biologically relevant stimuli.

A Quick guide to Love Spots: striking male-specific regions of the eye found in some insects that are used for detecting and chasing females.

Brain tauopathies are characterized by abnormal processing of tau protein. While somatodendritic tau mislocalization has attracted considerable attention in tauopathies, the role of tau pathology in axonal transport, connectivity and related dysfunctions remains obscure. We have previously shown using the squid giant synapse that presynaptic microinjection of recombinant human tau protein (htau42) results in failure of synaptic transmission. Here, we evaluated molecular mechanisms mediating this effect. Thus, the initial event, observed after htau42 presynaptic injection, was an increase in transmitter release. This event was mediated by calcium release from intracellular stores and was followed by a reduction in evoked transmitter release. The effect of htau42 on synaptic transmission was recapitulated by a peptide comprising the phosphatase-activating domain of tau, suggesting activation of phosphotransferases. Accordingly, findings indicated that htau42-mediated toxicity involves the activities of both GSK3 and Cdk5 kinases.

Exercise induces beneficial responses in the brain, which is accompanied by an increase in BDNF, a trophic factor associated with cognitive improvement and the alleviation of depression and anxiety. However, the exact mechanisms whereby physical exercise produces an induction in brain Bdnf gene expression are not well understood. While pharmacological doses of HDAC inhibitors exert positive effects on Bdnf gene transcription, the inhibitors represent small molecules that do not occur in vivo. Here, we report that an endogenous molecule released after exercise is capable of inducing key promoters of the Mus musculus Bdnf gene. The metabolite beta-hydroxybutyrate, which increases after prolonged exercise, induces the activities of Bdnf promoters, particularly promoter I, which is activity-dependent. We have discovered that the action of beta-hydroxybutyrate is specifically upon HDAC2 and HDAC3, which act upon selective Bdnf promoters. Moreover, the effects upon hippocampal Bdnf expression were observed after direct ventricular application of beta-hydroxybutyrate. Electrophysiological measurements indicate that beta-hydroxybutyrate causes an increase in neurotransmitter release, which is dependent upon the TrkB receptor. These results reveal an endogenous mechanism to explain how physical exercise leads to the induction of BDNF.

Neurons in area MT/V5 of the macaque visual cortex encode visual motion. Some cells are selective for the motion of oriented features (component direction-selective, CDS); others respond to the true direction of complex patterns (pattern-direction selective, PDS). There is a continuum of selectivity in MT, with CDS cells at one extreme and PDS cells at the other; we compute a pattern index that captures this variation. It is unknown how a neuron's pattern index is related to its other tuning characteristics. We therefore analyzed the responses of 792 MT cells recorded in the course of other experiments from opiate-anesthetized macaque monkeys, as a function of the direction, spatial frequency, drift rate, size, and contrast of sinusoidal gratings and of the direction and speed of random-dot textures. We also compared MT responses to those of 718 V1 cells. As expected, MT cells with higher pattern index tended to have stronger direction selectivity and broader direction tuning to gratings, and they responded better to plaids than to gratings. Strongly PDS cells also tended to have smaller receptive fields and stronger surround suppression. Interestingly, they also responded preferentially to higher drift rates and higher speeds of moving dots. The spatial frequency preferences of PDS cells depended strongly on their preferred temporal frequencies, whereas these preferences were independent in component-selective cells. Pattern direction selectivity is statistically associated with many response properties of MT cells but not strongly associated with any particular property. Pattern-selective signals are thus available in association with most other signals exported by MT.