Retrograde Degenerative Signaling Mediated by the p75 Neurotrophin Receptor Requires p150Glued Deacetylation by Axonal HDAC1.

During development, neurons undergo apoptosis if they do not receive adequate trophic support from tissues they innervate or when detrimental factors activate the p75 neurotrophin receptor (p75NTR) at their axon ends. Trophic factor deprivation (TFD) or activation of p75NTR in distal axons results in a retrograde degenerative signal. However, the nature of this signal and the regulation of its transport are poorly understood. Here, we identify p75NTR intracellular domain (ICD) and histone deacetylase 1 (HDAC1) as part of a retrograde pro-apoptotic signal generated in response to TFD or ligand binding to p75NTR in sympathetic neurons. We report an unconventional function of HDAC1 in retrograde transport of a degenerative signal and its constitutive presence in sympathetic axons. HDAC1 deacetylates dynactin subunit p150Glued, which enhances its interaction with dynein. These findings define p75NTR ICD as a retrograde degenerative signal and reveal p150Glued deacetylation as a unique mechanism regulating axonal transport.

Neurotrophin Responsiveness of Sympathetic Neurons Is Regulated by Rapid Mobilization of the p75 Receptor to the Cell Surface through TrkA Activation of Arf6.

The p75 neurotrophin receptor (p75NTR) plays an integral role in patterning the sympathetic nervous system during development. Initially, p75NTR is expressed at low levels as sympathetic axons project toward their targets, which enables neurotrophin-3 (NT3) to activate TrkA receptors and promote growth. Upon reaching nerve growth factor (NGF) producing tissues, p75NTR is upregulated, resulting in formation of TrkA-p75 complexes, which are high-affinity binding sites selective for NGF, thereby blunting NT3 signaling. The level of p75NTR expressed on the neuron surface is instrumental in regulating trophic factor response; however, the mechanisms by which p75NTR expression is regulated are poorly understood. Here, we demonstrate a rapid, translation independent increase in surface expression of p75NTR in response to NGF in rat sympathetic neurons. p75NTR was mobilized to the neuron surface from GGA3-postitive vesicles through activation of the GTPase Arf6, which was stimulated by NGF, but not NT3 binding to TrkA. Arf6 activation required PI3 kinase activity and was prevented by an inhibitor of the cytohesin family of Arf6 guanine nucleotide exchange factors. Overexpression of a constitutively active Arf6 mutant (Q67L) was sufficient to significantly increase surface expression of p75NTR even in the absence of NGF. Functionally, expression of active Arf6 markedly attenuated the ability of NT3 to promote neuronal survival and neurite outgrowth, whereas the NGF response was unaltered. These data suggest that NGF activation of Arf6 through TrkA is critical for the increase in p75NTR surface expression that enables the switch in neurotrophin responsiveness during development in the sympathetic nervous system.SIGNIFICANCE STATEMENT p75NTR is instrumental in the regulation of neuronal survival and apoptosis during development and is also implicated as a contributor to aberrant neurodegeneration in numerous conditions. Therefore, a better understanding of the mechanisms that mediate p75NTR surface availability may provide insight into how and why neurodegenerative processes manifest and reveal new therapeutic targets. Results from this study indicate a novel mechanism by which p75NTR can be rapidly shuttled to the cell surface from existing intracellular pools and explores a unique pathway by which NGF regulates the sympathetic innervation of target tissues, which has profound consequences for the function of these organs.

Decreased response monitoring in individuals with symptoms of trichotillomania.

Trichotillomania (TTM) was long classified as an impulse-control disorder; however, the many characteristics it shares with obsessive-compulsive disorder (OCD) led to its recategorization in the DSM-V. The present study aimed to assess and inform the taxonomic placement of TTM through an examination of its neural correlates. While research has consistently associated OCD with enhanced response monitoring, the present study investigated whether a similar neural process is associated with TTM. Undergraduates reporting TTM symptoms and controls performed a modified version of the flanker task, and their event-related potentials were examined for between-group differences in error-related negativity (ERN). Results confirm that individuals who have symptoms of hair pulling have significantly smaller ERNs than the control group. Smaller ERNs reflect decreased levels of response monitoring and support the idea that TTM is distinct from OCD.

Intravenous prenatal nicotine exposure increases orexin expression in the lateral hypothalamus and orexin innervation of the ventral tegmental area in adult male rats.

BACKGROUND: Approximately 18% of pregnant women continue to smoke tobacco cigarettes throughout pregnancy. Offspring exposed to tobacco smoke in utero exhibit a higher incidence of drug use in later stages of development relative to non-exposed children. Animal models indicate that prenatal nicotine (PN) exposure alone alters the development of the mesocorticolimbic dopamine (DA) system, which, in part, organizes motivated behavior and reward. The orexin/hypocretin neuropeptide system, which originates in the lateral hypothalamus (LH), projects to key areas of the mesocorticolimbic DA pathway. Previous research suggests that orexin exerts a major influence on motivation and reward. METHODS: The present experiments determined if intravenous (IV) PN exposure alters (1) the expression of orexin neurons and melanin-concentrating hormone (MCH; positive control) in the LH; and (2) orexin projections from the LH onto DA neurons in the ventral tegmental area (VTA). Dams were injected with IV nicotine (0.05 mg/kg/injection) or saline 3×/day during gestational days 8-21. Tissues from adult male offspring (∼130 days) were examined using immunohistochemistry. RESULTS: Relative to controls, offspring of IV PN exposure showed (1) increased numbers of orexin neurons in the LH, and no changes in the expression of MCH; and (2) increased orexin appositions on DA cells in the VTA. CONCLUSION: The findings indicate that the influence of PN exposure is enduring, and suggests that the PN-induced modification of orexin expression on mesolimbic circuitry may contribute to the reported changes in motivated behaviors related to food and drug reward observed in offspring prenatally exposed to nicotine.

Cognitive and electrophysiological correlates of the bilingual stroop effect.

The color word Stroop effect in bilinguals is commonly half the magnitude when the written and naming languages are different (between) than when they are the same (within). This between-within language Stroop difference (BWLS) is likened to a response set effect, with greater response conflict for response relevant than irrelevant words. The nature of the BWLS was examined using a bilingual Stroop task. In a given block (Experiment 1), color congruent and incongruent words appeared in the naming language or not (single), or randomly in both languages (mixed). The BWLS effect was present for both balanced and unbalanced bilinguals, but only partially supported a response set explanation. As expected, color incongruent trials during single language blocks, lead to slower response times within than between languages. However, color congruent trials during mixed language blocks led to slower times between than within languages, indicating that response-irrelevant stimuli interfered with processing. In Experiment 2, to investigate the neural timing of the BWLS effect, event related potentials were recorded while balanced bilinguals named silently within and between languages. Replicating monolingual findings, an N450 effect was observed with larger negative amplitude for color incongruent than congruent trials (350-550 ms post-stimulus onset). This effect was equivalent within and between languages, indicating that color words from both languages created response conflict, contrary to a strict response set effect. A sustained negativity (SN) followed with larger amplitude for color incongruent than congruent trials, resolving earlier for between than within language Stroop. This effect shared timing (550-700 ms), but not morphology or scalp distribution with the commonly reported sustained potential. Finally, larger negative amplitude (200-350 ms) was observed between than within languages independent of color congruence. This negativity, likened to a no-go N2, may reflect processes of inhibitory control that facilitate the resolution of conflict at the SN, while the N450 reflects parallel processing of distracter words, independent of response set (or language). In sum, the BWLS reflects brain activity over time with contributions from language and color conflict at different points.

Hippocampal neurotransmitter efflux during one-trial novel object recognition in rats.

Several lines of evidence point to a role for the hippocampal formation and contiguous temporal lobe structures in a variety of learning and memory paradigms. Presumably, these cognitive phenomena are mediated (and accompanied) by dynamic changes in neurochemical transmission that may differ between learning and recall phases. However, the neurotransmitter correlates of most memory-related tasks have not been thoroughly investigated. Here we used a one-trial object recognition paradigm paired with in vivo microdialysis to assess hippocampal acetylcholine (ACh), glutamate and GABA efflux when rats were exposed to familiar objects, and when given the option to explore familiar and novel objects. Rats preferentially explored the novel object over the familiar one when presented with the option. Regardless of object familiarity, object exploration was accompanied by an increase in hippocampal ACh efflux, while GABA efflux was unaffected. However, glutamate efflux was not increased above baseline levels by presentation of familiar objects, but was significantly enhanced in the presence of the novel object. These data suggest that the hippocampus, and in particular, hippocampal glutamate, may be involved in memory processes during novelty recognition paradigms.

Aging-related deficits in orexin/hypocretin modulation of the septohippocampal cholinergic system.

The medial septum (MS) of the basal forebrain contains cholinergic neurons that project to the hippocampus, support cognitive function, and are implicated in age-related cognitive decline. Hypothalamic orexin/hypocretin neurons innervate and modulate basal forebrain cholinergic neurons and provide direct inputs to the hippocampus. However, the precise role of orexin in modulating hippocampal cholinergic transmission--and how these interactions are altered in aging--is unknown. Here, orexin A was administered to CA1 and the MS of young (3-4 months) and aged (27-29 months) Fisher 344/Brown Norway rats, and hippocampal acetylcholine efflux was analyzed by in vivo microdialysis. At both infusion sites, orexin A dose-dependently increased hippocampal acetylcholine in young, but not aged rats. Moreover, immunohistochemical characterization of the MS revealed no change in cholinergic cell bodies in aged animals, but a significant decrease in orexin fiber innervation to cholinergic cells. These findings indicate that: (1) Orexin A modulates hippocampal cholinergic neurotransmission directly and transsynaptically in young animals, (2) Aged animals are unresponsive to orexin A, and (3) Aged animals undergo an intrinsic reduction in orexin innervation to cholinergic cells within the MS. Alterations in orexin regulation of septohippocampal cholinergic activity may contribute to age-related dysfunctions in arousal, learning, and memory.

Interneuron loss reduces dendritic inhibition and GABA release in hippocampus of aged rats.

Aging is associated with impairments in learning and memory and a greater incidence of limbic seizures. These changes in the aged brain have been associated with increased excitability of hippocampal pyramidal cells caused by a reduced number of gamma-aminobutyric acid-ergic (GABAergic) interneurons. To better understand these issues, we performed cell counts of GABAergic interneurons and examined GABA efflux and GABAergic inhibition in area CA1 of the hippocampus of young (3-5 months) and aged (26-30 months) rats. Aging significantly reduced high K(+)/Ca(2+)-evoked GABA, but not glutamate efflux in area CA1. Immunostaining revealed a significant loss of GABAergic interneurons, but not inhibitory boutons in stratum oriens and stratum lacunosum moleculare. Somatostatin-immunoreactive oriens-lacunosum moleculare (O-LM) cells, but not parvalbumin-containing interneurons were selectively lost. Oriens-lacunosum moleculare cells project to distal dendrites of CA1 pyramidal cells, providing dendritic inhibition. Accordingly, inhibition of dendritic input to CA1 from entorhinal cortex was selectively reduced. These findings suggest that the age-dependent loss of interneurons impairs dendritic inhibition and dysregulates entorhinal cortical input to CA1, potentially contributing to cognitive impairment and seizures.

Native experience with a tone language enhances pitch discrimination and the timing of neural responses to pitch change.

Native tone language experience has been linked with alterations in the production and perception of pitch in language, as well as with the brain response to linguistic and non-linguistic tones. Here we use two experiments to address whether these changes apply to the discrimination of simple pitch changes and pitch intervals. Event related potentials (ERPs) were recorded from native Mandarin speakers and a control group during a same/different task with pairs of pure tones differing only in pitch height, and with pure tone pairs differing only in interval distance. Behaviorally, Mandarin speakers were more accurate than controls at detecting both pitch and interval changes, showing a sensitivity to small pitch changes and interval distances that was absent in the control group. Converging evidence from ERPs obtained during the same tasks revealed an earlier response to change relative to no-change trials in Mandarin speakers, as well as earlier differentiation of trials by change direction relative to controls. These findings illustrate the cross-domain influence of language experience on the perception of pitch, suggesting that the native use of tonal pitch contours in language leads to a general enhancement in the acuity of pitch representations.