bluuebunny/crossref_metadata_2025 huggingface dataset:
Categorically Distinct Acute Stressors Elicit Dissimilar Transcriptional Profiles in the Paraventricular Nucleus of the Hypothalamus
Authors: Reyes Teresa M. , Walker John R. , DeCino Casey , Hogenesch John B. , Sawchenko Paul E.
Published: April 2018

The paraventricular hypothalamic nucleus (PVH) is a key site for integrating neuroendocrine, autonomic, and behavioral adjustments to diverse homeostatic challenges, including “physiological” (e.g., infection or hemorrhage) and “emotional” [e.g., restraint (RST) or footshock] stresses. Both types of challenges ultimately converge to activate common response systems represented in PVH, including the hypothalamo–pituitary–adrenal axis and the sympathoadrenal system. Oligonucleotide microarrays (U74A; Affymetrix, Santa Clara, CA) were used to compare and contrast gene expression profiles in the PVH elicited at 1 and 3 hr after acute exposure to representative physiological [intraperitoneal injection of 10 μg lipopolysaccharide (LPS)] and emotional (30 min RST) stressors. In general, the two challenges recruited relatively few genes in common, with the degree of overlap varying across functional classes of genes. The greatest degree of commonality was seen among signaling molecules and neuropeptides, whereas transcription factors upregulated by RST and LPS were largely distinct. Unexpectedly, RST induced a number of immune-related molecules, which were not regulated by LPS. Hybridization histochemical analyses localized a subset of responsive transcripts to the PVH and/or immediately adjoining regions. Immunerelated molecules in particular distributed broadly to vascular and other barrier-associated cell types. These global transcriptional profiles inform the search for early (transcription factors) and late (target genes) mechanisms in the modulation of PVH, and generalized CNS, responses to categorically distinct stressors.
Independent Projection Streams from Macaque Striate Cortex to the Second Visual Area and Middle Temporal Area
Authors: Sincich Lawrence C. , Horton Jonathan C.
Published: April 2018

The interareal wiring of the neocortex is usually depicted as a network of single point-to-point connections, often side-stepping the possibility that some neurons may project to multiple cortical areas. The prevalence of such neurons is unknown; if they are abundant, cortical circuits are more likely to be connectionally diffuse. We used a dual-tracer approach to determine whether single neurons in the macaque primary visual cortex (V1) project to two extrastriate areas, the second visual area (V2) and the middle temporal area (MT). We found two large intermingled groups of single-labeled neurons in layer 4B of V1 projecting independently to either V2 or MT. A third, sparser group of double-labeled neurons projected to both areas; we termed these manifold neurons. We also found that MT-projecting cells were distributed indiscriminately with respect to cytochrome oxidase compartment in layer 4B, revealing a subpopulation that provides a potential source of patch input from V1 to MT. The results demonstrate that primary sensory cortices can use multiple projection strategies to distribute signals to higher areas, and suggest that feedforward projections may route signals with more specificity than feedback pathways.
Cyclic Estrogen Replacement Improves Cognitive Function in Aged Ovariectomized Rhesus Monkeys
Authors: Rapp Peter R. , Morrison John H. , Roberts Jeffrey A.
Published: April 2018

Among the identified risks and benefits of hormone-replacement therapy, the effects of treatment on cognitive function in postmenopausal women have proved difficult to define. Here we conducted a controlled, prospective analysis in a nonhuman primate model to test whether surgical menopause and estrogen replacement influence the cognitive outcome of normal aging. Sixteen aged rhesus monkeys were ovariectomized, and throughout the course of subsequent neuropsychological assessment, half received a regimen of low-dose, cyclic estradiol replacement. Hormone treatment substantially reversed the marked age-related impairment vehicle-injected monkeys exhibited on a delayed response test of spatial working memory. Modest improvement was also observed on a delayed nonmatching-to-sample recognition memory task. In contrast, ovariectomy exacerbated age-related deficits in object discrimination learning; the magnitude of this effect was equivalent among vehicle- and estrogen-treated monkeys. Together, these results demonstrate that ovarian hormone status can broadly influence normal cognitive aging in monkeys, affecting capacities mediated by multiple brain regions, including the prefrontal cortex and the medial temporal lobe memory system. The animal model established here should enable progress toward defining the neurobiological mechanisms that mediate the beneficial effects of estrogen on age-related cognitive decline in primates.
Propagation of Correlated Activity through Multiple Stages of a Neural Circuit
Authors: Kimpo Rhea R. , Theunissen Frederic E. , Doupe Allison J.
Published: April 2018

The timing of spikes can carry information, for instance, when the temporal pattern of firing across neurons results in correlated activity. However, in part because central synapses are unreliable, correlated activity has not been observed to propagate through multiple subsequent stages in neural circuits, although such propagation has frequently been used in theoretical models. Using simultaneous single-unit and multiunit recordings from two or three vocal control nuclei of songbirds, measurement of coherency and time delays, and manipulation of neural activity, we provide evidence here for preserved correlation of activity through multiple steps of the neural circuit for song, including a basal ganglia circuit and its target vocal motor pathway. This suggests that these pathways contain highly functionally interconnected neurons and represent a neural architecture that can preserve information about the timing of firing of groups of neurons. Because the interaction of these song pathways is critical to vocal learning, the preserved correlation of activity may be important to the learning and production of sequenced motor acts and could be a general feature of basal ganglia–cortical interaction.
High Threshold for Induction of the Stress Response in Motor Neurons Is Associated with Failure to Activate HSF1
Authors: Batulan Zarah , Shinder Gayle A. , Minotti Sandra , He Bei Ping , Doroudchi Mohammad M. , Nalbantoglu Josephine , Strong Michael J. , Durham Heather D.
Published: April 2018

Heat shock protein 70 (Hsp70) protects cultured motor neurons from the toxic effects of mutations in Cu/Zn-superoxide dismutase (SOD-1), which is responsible for a familial form of the disease, amyotrophic lateral sclerosis (ALS). Here, the endogenous heat shock response of motor neurons was investigated to determine whether a high threshold for activating this protective mechanism contributes to their vulnerability to stresses associated with ALS. When heat shocked, cultured motor neurons failed to express Hsp70 or transactivate a green fluorescent protein reporter gene driven by the Hsp70 promoter, although Hsp70 was induced in glial cells. No increase in Hsp70 occurred in motor neurons after exposure to excitotoxic glutamate or expression of mutant SOD-1 with a glycine→ alanine substitution at residue 93 (G93A), nor was Hsp70 increased in spinal cords of G93A SOD-1 transgenic mice or sporadic or familial ALS patients. In contrast, strong Hsp70 induction occurred in motor neurons with expression of a constitutively active form of heat shock transcription factor (HSF)-1 or when proteasome activity was sufficiently inhibited to induce accumulation of an alternative transcription factor HSF2. These results indicate that the high threshold for induction of the stress response in motor neurons stems from an impaired ability to activate the main heat shock–stress sensor, HSF1.
Post-Traumatic Hyperexcitability Is Not Caused by Impaired Buffering of Extracellular Potassium
Authors: Santhakumar Vijayalakshmi , Voipio Juha , Kaila Kai , Soltesz Ivan
Published: April 2018

Impaired extracellular potassium buffering has been proposed as one of the major mechanisms underlying the increased risk for temporal lobe epilepsy after brain injury (D'Ambrosio et al., 1999). The present study systematically tested this hypothesis by measuring the resting [K+]oand recovery of the stimulation-evoked [K+]oincreases in the dentate gyrus after experimental head trauma, using a combination of whole-cell recordings and ion-selective microelectrode recordings in rat hippocampal slices. Despite the presence of hyperexcitability, the resting [K+]owas not increased after injury. The faster rate of increase and larger amplitude of the orthodromically evoked [K+]oelevation after head trauma occurred in association with a greater population spike with shorter response latency. Contrary to the assumption in previous studies that the evoked activity in control and injured neuronal circuits is the same during antidromic activation, stimulation of granule cell axons in glutamate receptor antagonists evoked a greater [K+]oincrease and a larger population spike. Although perforant path stimulation resulted in a larger [K+]oelevation after injury, the rate of clearance of the [K+]otransients evoked either by neuronal activity or by external application of potassium was not compromised. The [K+]oincrease evoked by activation of the presynaptic afferents in isolation was not increased. In addition, the postsynaptic neuronal depolarization and firing evoked by exogenous potassium application was decreased after trauma.

These results show that the regulation of [K+]ois not impaired after injury and indicate that the larger [K+]oincrease evoked by neuronal activity is a consequence, rather than the primary mechanism underlying post-traumatic hyperexcitability.
Actin Filament-Stabilizing Protein Tropomyosin Regulates the Size of Dendritic Fields
Authors: Li Wenjun , Gao Fen-Biao
Published: April 2018

Dendritic arbors of different neuronal subtypes cover distinct spatial territories, known as dendritic fields, to receive specific inputs in a nervous system. How the size of dendritic fields is determined by cell-intrinsic factors during development remains primarily unknown. To address this issue, we used theDrosophilaembryonic peripheral nervous system. In each hemisegment, six dorsal cluster dendritic arborization (DA) neurons elaborate stereotypic dendritic branching patterns underneath the epidermis. Here we report the identification of loss-of-function mutations in the tropomyosin II gene (TmII) that result in expanded dendritic fields of DA neurons. Mosaic analysis with a repressible cell marker demonstrated thatTmIIfunctions in a cell-autonomous manner to control the formation of dendritic fields. Furthermore, we show thatTmIIgenetically interacted withflamingo, a gene encoding a membrane receptor-like molecule that affects dendritic growth.TmIIencodes multiple isoforms of a protein that stabilizes actin filaments. Our findings suggest that tropomyosin helps control the size of dendritic fields by regulating actin cytoskeletal dynamics.
Proteinase-Activated Receptor-2 Mediates Itch: A Novel Pathway for Pruritus in Human Skin
Authors: Steinhoff Martin , Neisius Ulrich , Ikoma Akihiko , Fartasch Manigé , Heyer Gisela , Skov Per S. , Luger Thomas A. , Schmelz Martin
Published: April 2018

We examined whether neuronal proteinase-activated receptor-2 (PAR-2) may be involved in pruritus of human skin. The endogenous PAR-2 agonist tryptase was increased up to fourfold in atopic dermatitis (AD) patients. PAR-2 was markedly enhanced on primary afferent nerve fibers in skin biopsies of AD patients. Intracutaneous injection of endogenous PAR-2 agonists provoked enhanced and prolonged itch when applied intralesionally. Moreover, itch upon mast cell degranulation was abolished by local antihistamines in controls but prevailed in AD patients. Thus, we identified enhanced PAR-2 signaling as a new link between inflammatory and sensory phenomena in AD patients. PAR-2 therefore represents a promising therapeutic target for the treatment of cutaneous neurogenic inflammation and pruritus.
Estradiol Regulates the Slow Ca2+-Activated K+Current in Hippocampal Pyramidal Neurons
Authors: Carrer Hugo F. , Araque Alfonso , Buño Washington
Published: April 2018

The slow Ca2+-activated K+current (sIAHP) was recorded in CA1 pyramidal neurons in hippocampal slices obtained from ovariectomized (OVX) or sham OVX (control) female rats. The sIAHPwas significantly larger in cells from OVX rats than in cells from control rats. Superfusion with 5–100 nm17β-estradiol (E2) caused a progressive decrease in the sIAHPin cells from OVX rats but not in cells from control rats. In slices from OVX rats injected with 10 μg of E2 24 and 48 hr before they were killed, superfusion with E2 did not modify the sIAHP. In neurons from OVX rats, but not in neurons from control rats, E2 significantly increased both the number of action potentials and the burst duration generated by depolarizing pulses. The inactive isomer 17α-estradiol had no effect. The impermeant protein conjugate E2—BSA was as effective as free E2 at decreasing the sIAHP. Ca2+spikes were also depressed by E2 in neurons from OVX rats, but not in control rats. A decrease in the intracellular Ca2+signal, correlating with the inhibition of the Ca2+spike and sIAHPproduced by E2, was observed only in neurons from OVX rats. Our results indicate that ovariectomy increases the sIAHPand depresses excitability, whereas bath application or priming with E2 decreases the sIAHP, thus promoting excitability. These effects of E2 on the sIAHPand excitability, which are stereospecific and presumably mediated by membrane-bound receptors, could contribute to the hormonal regulation of synaptic plasticity and epileptiform activity as well as to learning and cognitive abilities dependent on the function of hippocampal neural circuits.
Clozapine Reverses Hyperthermia and Sympathetically Mediated Cutaneous Vasoconstriction Induced by 3,4-Methylenedioxymethamphetamine (Ecstasy) in Rabbits and Rats
Authors: Blessing W. W. , Seaman B. , Pedersen N. P. , Ootsuka Y.
Published: April 2018

Life-threatening hyperthermia occurs in some individuals taking 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). In rabbits, sympathetically mediated vasoconstriction in heat-exchanging cutaneous beds (ear pinnae) contributes to MDMA-elicited hyperthermia. We investigated whether MDMA-elicited cutaneous vasoconstriction and hyperthermia are reversed by clozapine and olanzapine, atypical antipsychotic agents. Ear pinna blood flow and body temperature were measured in conscious rabbits; MDMA (6 mg/kg, i.v.) was administered; and clozapine (0.1–5 mg/kg, i.v.) or olanzapine (0.5 mg/kg, i.v.) was administered 15 min later. One hour after MDMA, temperature was 38.7 ± 0.5°C in 5 mg/kg clozapine-treated rabbits and 39.0 ± 0.2°C in olanzapine-treated rabbits, less than untreated animals (41.5 ± 0.3°C) and unchanged from pre-MDMA values. Ear pinna blood flow increased from the MDMA-induced near zero level within 5 min of clozapine or olanzapine administration. Clozapine-induced temperature and flow responses were dose-dependent. In urethane-anesthetized rabbits, MDMA (6 mg/kg, i.v.) increased ear pinna postganglionic sympathetic nerve discharge to 217 ± 33% of the pre-MDMA baseline. Five minutes after clozapine (1 mg/kg, i.v.) discharge was reduced to 10 ± 4% of the MDMA-elicited level. In conscious rats made hyperthermic by MDMA (10 mg/kg, s.c.), body temperature 1 hr after clozapine (3 mg/kg, s.c.) was 36.9 ± 0.5°C, <38.6 ± 0.3°C (Ringer's solution-treated) and not different from the pre-MDMA level. One hour after clozapine, rat tail blood flow was 24 ± 3 cm/sec, greater than both flow in Ringer's solution-treated rats (8 ± 1 cm/sec) and the pre-MDMA level (17 ± 1 cm/sec). Clozapine and olanzapine, by interactions with 5-HT receptors or by other mechanisms, could reverse potentially fatal hyperthermia and cutaneous vasoconstriction occurring in some humans after ingestion of MDMA.
Topographic Plasticity in Primary Visual Cortex Is Mediated by Local Corticocortical Connections
Authors: Calford Mike B. , Wright Layne L. , Metha Andrew B. , Taglianetti Vivian
Published: April 2018

The placement of monocular laser lesions in the adult cat retina produces a lesion projection zone (LPZ) in primary visual cortex (V1) in which the majority of neurons have a normally located receptive field (RF) for stimulation of the intact eye and an ectopically located RF (displaced to intact retina at the edge of the lesion) for stimulation of the lesioned eye. Animals that had such lesions for 14-85 d were studied under halothane and nitrous oxide anesthesia with conventional neurophysiological recording techniques and stimulation of moving light bars. Previous work suggested that a candidate source of input, which could account for the development of the ectopic RFs, was long-range horizontal connections within V1. The critical contribution of such input was examined by placing a pipette containing the neurotoxin kainic acid at a site in the normal V1 visual representation that overlapped with the ectopic RF recorded at a site within the LPZ. Continuation of well defined responses to stimulation of the intact eye served as a control against direct effects of the kainic acid at the LPZ recording site. In six of seven cases examined, kainic acid deactivation of neurons at the injection site blocked responsiveness to lesioned-eye stimulation at the ectopic RF for the LPZ recording site. We therefore conclude that long-range horizontal projections contribute to the dominant input underlying the capacity for retinal lesion-induced plasticity in V1.
Individual Cerebellar Purkinje Cells Express Different cGMP Phosphodiesterases (PDEs):In VivoPhosphorylation of cGMP-Specific PDE (PDE5) as an Indicator of cGMP-dependent protein kinase (PKG) Activation
Authors: Shimizu-Albergine Masami , Rybalkin Sergei D. , Rybalkina Irina G. , Feil Robert , Wolfsgruber Wiebke , Hofmann Franz , Beavo Joseph A.
Published: April 2018

The nitric oxide (NO)-cGMP pathway has been implicated as playing a crucial role in the induction of cerebellar long-term depression (LTD). The amplitude and duration of the cGMP signal is controlled by cyclic nucleotide phosphodiesterases (PDEs). Here we identify PDE5 and PDE1B as the two major cGMP-hydrolyzing PDEs specifically and differentially expressed in the Purkinje neurons of mouse cerebellum. PDE5 was found in all Purkinje neurons, whereas PDE1B was detected only in a subset of these cells, suggesting that individual Purkinje cells may differentially regulate cGMP, depending on the PDE isozymes expressed.

Although expression of guanylate cyclase and/or cGMP-dependent protein kinase (PKG) in Purkinje cells have been reported, neither cGMP accumulation nor PKG activation in these cellsin vivohas been demonstrated. To determine if changes in PKG activation and PDE5 regulation occurin vivowe have examined the phosphorylation of PDE5 in mouse cerebellar Purkinje cells by immunocytochemistry and Western blot analyses using a phosphospecific PDE5 antibody. Injection of sodium nitroprusside or selective PKG activators into the lateral ventricle of mouse brain induced PDE5 phosphorylationin vivo, but was completely missing in Purkinje cell-specific PKG I knock-out mice. In cerebellar slices, treatment with sildenafil or IBMX led to different levels of phospho-PDE5 accumulation and activation of PDE5. These results suggest that phosphorylation of PDE5 in Purkinje neurons after cGMP-PKG activation performs a critical role in the termination of the cGMP signal during LTD progression; moreover, PDE5 phosphorylation may be used as anin vivoindicator for PKG activation.
Functional Specialization within Medial Frontal Cortex of the Anterior Cingulate for Evaluating Effort-Related Decisions
Authors: Walton Mark E. , Bannerman David M. , Alterescu Karin , Rushworth Matthew F. S.
Published: April 2018

The rat medial frontal cortex (MFC) has been implicated in allowing animals to work harder to receive larger rewards. However, it is unknown what role the individual MFC regions [anterior cingulate cortex (ACC) and prelimbic-infralimbic cortex (PL-IL)] play in such decision making. To investigate this, we trained rats on a T-maze cost-benefit task with two possible courses of action, shown previously to be affected by complete MFC lesions. One response involved climbing a 30 cm barrier to obtain a large quantity of reward (high cost-high reward), whereas the other had a lower energetic demand but also a smaller reward gain (low cost-low reward). Before surgery, all animals preferred to select the high cost-high reward option. However, after excitotoxic ACC lesions, there was a complete reversal of behavior, with the ACC group selecting the low cost-low reward response on nearly every trial. In contrast, both control animals and rats with PL-IL lesions continued to choose to climb the barrier for the larger reward. When the same rats were tested on a delayed match-to-sample paradigm however, it was the PL-IL group that was significantly impaired at learning the response rule, with the performance of ACC rats being comparable with controls. This double dissociation indicates that the ACC is the important region within the MFC when evaluating how much effort to expend for a specific reward.
Mechanical Characteristics of Rat Vibrissae: Resonant Frequencies and Damping in Isolated Whiskers and in the Awake Behaving Animal
Authors: Hartmann Mitra J. , Johnson Nicholas J. , Towal R. Blythe , Assad Christopher
Published: April 2018

We investigated the natural resonance properties and damping characteristics of rat macrovibrissae (whiskers). Isolated whiskers rigidly fixed at the base showed first-mode resonance peaks between 27 and 260 Hz, principally depending on whisker length. These experimentally measured resonant frequencies were matched using a theoretical model of the whisker as a conical cantilever beam, with Young's modulus as the only free parameter. The best estimate for Young's modulus was ∼3-4 GPa. Results of both vibration and impulse experiments showed that the whiskers are strongly damped, with damping ratios between 0.11 and 0.17. In the behaving animal, whiskers that deflected past an object were observed to resonate but were damped significantly more than isolated whiskers. The time course of damping varied depending on the individual whisker and the phase of the whisking cycle, which suggests that the rat may modulate biomechanical parameters that affect damping. No resonances were observed for whiskers that did not contact the object or during free whisking in air. Finally, whiskers on the same side of the face were sometimes observed to move in opposite directions over the full duration of a whisk. We discuss the potential roles of resonance during natural exploratory behavior and specifically suggest that resonant oscillations may be important in the rat's tactile detection of object boundaries.
Drebrin-Dependent Actin Clustering in Dendritic Filopodia Governs Synaptic Targeting of Postsynaptic Density-95 and Dendritic Spine Morphogenesis
Authors: Takahashi Hideto , Sekino Yuko , Tanaka Satoshi , Mizui Toshiyuki , Kishi Shoji , Shirao Tomoaki
Published: April 2018

Dendritic spines have two major structural elements: postsynaptic densities (PSDs) and actin cytoskeletons. PSD proteins are proposed to regulate spine morphogenesis. However, other molecular mechanisms should govern spine morphogenesis, because the initiation of spine morphogenesis precedes the synaptic clustering of these proteins. Here, we show that synaptic clustering of drebrin, an actin-binding protein highly enriched in dendritic spines, governs spine morphogenesis. We immunocytochemically analyzed developing hippocampal neurons of low-density cultures. Filopodia-like dendritic protrusions were classified into two types: diffuse-type filopodia, which have diffuse distribution of drebrin, and cluster-type filopodia, which have drebrin clusters with filamentous actin (F-actin). Most cluster-type filopodia were synaptic filopodia. Postsynaptic drebrin clusters were found in both most synaptic filopodia and spines. Postsynaptic PSD-95 clusters, however, were found in only one-half of synaptic filopodia but in most spines. These data indicate that cluster-type filopodia are not mature spines but their precursors. Suppression of the upregulation of drebrin adult isoform (drebrin A) by antisense oligonucleotides against it attenuated synaptic clustering of PSD-95, as well as clustering of drebrin and F-actin. Furthermore, the restoration of drebrin A expression by injection of the expression vectors of drebrin A tagged with green fluorescent protein into the neurons treated with the antisense oligonucleotides induced synaptic reclustering of PSD-95 on clusters of the labeled drebrin A. These data indicated that the synaptic clustering of drebrin is necessary for that of PSD-95 in developing neurons. Together, these data suggest that synaptic clustering of drebrin is an essential step for spine morphogenesis.
Distribution and Properties of Functional Postsynaptic Kainate Receptors on Neocortical Layer V Pyramidal Neurons
Authors: Eder Matthias , Becker Klaus , Rammes Gerhard , Schierloh Anja , Azad Shahnaz Christina , Zieglgänsberger Walter , Dodt Hans-Ulrich
Published: April 2018

The distribution of glutamate receptor subtypes on the surface of neurons is highly relevant for synaptic transmission and signal processing. In the present study we investigated the location and properties of functional kainate receptors (KARs) on the somatodendritic membrane of rat neocortical layer V pyramidal neurons. Infrared-guided laser stimulation was used to apply glutamate photolytically to the soma and various sites along the apical dendrite. Electrical currents, resulting from the activation of pharmacologically isolated KARs, were measured by whole-cell patch-clamp recording. In addition, KARs on somatic and dendritic outside-out patches were activated while still within the brain tissue. We found that functional KARs are located on the entire somatodendritic membrane that was examined. Fast kinetics, a linearI-Vrelationship, and a relatively high single-channel conductance are characteristic features of these receptors. We provide evidence that the unitary properties of somatic and dendritic KARs are identical. Regarding the subcellular distribution of KARs, our results indicate that the density of these receptors increases toward the distal dendrite. They are located mainly at extrasynaptic sites but also mediate fast synaptic signaling triggered by afferent stimulation. The differential distribution speaks in favor of a selective targeting of KARs on central neurons and may reflect a mechanism for a location-dependent regulation of synaptic efficacy. Furthermore, it is feasible to assume that extrasynaptic KARs could be activated by a “spillover” of synaptically released glutamate, ambient glutamate in the CSF, or glutamate released from adjacent astrocytes.
Brain-Derived Neurotrophic Factor val66met Polymorphism Affects Human Memory-Related Hippocampal Activity and Predicts Memory Performance
Authors: Hariri Ahmad R. , Goldberg Terry E. , Mattay Venkata S. , Kolachana Bhaskar S. , Callicott Joseph H. , Egan Michael F. , Weinberger Daniel R.
Published: April 2018

BDNF plays a critical role in activity-dependent neuroplasticity underlying learning and memory in the hippocampus. A frequent single nucleotide polymorphism in the targeting region of the human BDNF gene (val66met) has been associated with abnormal intracellular trafficking and regulated secretion of BDNF in cultured hippocampal neurons transfected with the met allele. In addition, the met allele has been associated with abnormal hippocampal neuronal function as well as impaired episodic memory in human subjects, but a direct effect of BDNF alleles on hippocampal processing of memory has not been demonstrated. We studied the relationship of the BDNF val66met genotype and hippocampal activity during episodic memory processing using blood oxygenation level-dependent functional magnetic resonance imaging and a declarative memory task in healthy individuals. Met carriers exhibited relatively diminished hippocampal engagement in comparison with val homozygotes during both encoding and retrieval processes. Remarkably, the interaction between the BDNF val66met genotype and the hippocampal response during encoding accounted for 25% of the total variation in recognition memory performance. These data implicate a specific genetic mechanism for substantial normal variation in human declarative memory and suggest that the basic effects of BDNF signaling on hippocampal function in experimental animals are important in humans.
Rapid Critical Period Induction by Tonic Inhibition in Visual Cortex
Authors: Iwai Youichi , Fagiolini Michela , Obata Kunihiko , Hensch Takao K.
Published: April 2018

Mice lacking a synaptic isoform of glutamic acid decarboxylase (GAD65) do not exhibit ocular dominance plasticity unless an appropriate level of GABAergic transmission is restored by direct infusion of benzodiazepines into the brain. To better understand how intracortical inhibition triggers experience-dependent changes, we dissected the precise timing requirement for GABA function in the monocular deprivation (MD) paradigm.

Diazepam (DZ) or vehicle solution was infused daily before and/or during 4 d of MD in GAD65 knock-out mice. Extracellular single-unit recordings from the binocular zone of visual cortex were performed at the end of deprivation. We found that a minimum treatment of 2 d near the beginning of MD was sufficient to fully activate plasticity but did not need to overlap the deprivation per se. Extended delay after DZ infusion eventually led to loss of plasticity accompanied by improved intrinsic inhibitory circuit function. Two day DZ treatment just after eye opening similarly closed the critical period prematurely in wild-type mice.

Raising wild-type mice in complete darkness from birth delayed the peak sensitivity to MD as in other mammals. Interestingly, 2 d DZ infusion in the dark also closed the critical period, whereas equally brief light exposure during dark-rearing had no such effect. Thus, enhanced tonic signaling through GABAAreceptors rapidly creates a milieu for plasticity within neocortex capable of triggering a critical period for ocular dominance independent of visual experience itself.
β-Amyloid Regulation of Presynaptic Nicotinic Receptors in Rat Hippocampus and Neocortex
Authors: Dougherty John J. , Wu Jianlin , Nichols Robert A.
Published: April 2018

Alteration by β-amyloid (Aβ) of signaling via nicotinic acetylcholine receptors (nAChRs) has been implicated in the early stages of Alzheimer's disease. nAChRs function both post- and presynaptically in the nervous system; however, little is known about the functional consequence of the interaction of Aβ with these receptors, particularly those on presynaptic nerve terminals. In view of the strong correlation between loss of synaptic terminals and dementia, together with the reduction in nAChRs in Alzheimer's disease, the possibility exists that presynaptic nAChRs may be targets for Aβ. To explore this possibility, we assessed the effect of Aβ peptides on nicotine-evoked changes in presynaptic Ca2+level via confocal imaging of isolated presynaptic nerve endings from rat hippocampus and neocortex. Aβ1-42appeared to inhibit presynaptic nAChR activation by nicotine. Surprisingly, picomolar Aβ1-42was found to directly evoke sustained increases in presynaptic Ca2+via nAChRs, revealing that the apparent inhibitory action of Aβ1-42was the result of an occlusion of nicotine to further stimulate the receptors. The direct effect of Aβ was found to be sensitive to α-bungarotoxin, mecamylamine, and dihydro-β-erythroidine, indicating involvement of α7-containing nAChRs and non-α7-containing nAChRs. Prior depolarization strongly attenuated subsequent Aβ-evoked responses in a manner dependent on the amplitude of the initial presynaptic Ca2+increase, suggesting that nerve activity or Ca2+channel density may control the impact of Aβ on presynaptic nerve terminal function. Together, these results suggest that the sustained increases in presynaptic Ca2+evoked by Aβ may underlie disruptions in neuronal signaling via nAChRs in the early stages of Alzheimer's disease.
Brain Activity Evoked by the Perception of Human Walking: Controlling for Meaningful Coherent Motion
Authors: Pelphrey Kevin A. , Mitchell Teresa V. , McKeown Martin J. , Goldstein Jeremy , Allison Truett , McCarthy Gregory
Published: April 2018

Many functional neuroimaging studies of biological motion have used as stimuli point-light displays of walking figures and compared the resulting activations with those evoked by the same display elements moving in a random or noncoherent manner. Although these studies have established that biological motion activates the superior temporal sulcus (STS), the use of random motion controls has left open the possibility that coordinated and meaningful nonbiological motion might activate these same brain regions and thus call into question their specificity for processing biological motion. Here we used functional magnetic resonance imaging and an anatomical region-of-interest approach to test a hierarchy of three questions regarding activity within the STS. First, by comparing responses in the STS with animations of human and robot walking figures, we determined (1) that the STS is sensitive to biological motion itself, not merely to the superficial characteristics of the stimulus. Then we determined that the STS responds more strongly to biological motion (as conveyed by the walking robot) than to (2) a nonmeaningful but complex nonbiological motion (a disjointed mechanical figure) and (3) a complex and meaningful nonbiological motion (the movements of a grandfather clock). In subsequent whole-brain voxel-based analyses, we confirmed robust STS activity that was strongly right lateralized. In addition, we observed significant deactivations in the STS that differentiated biological and nonbiological motion. These voxel-based analyses also revealed regions of motion-related positive activity in other brain regions, including MT or V5, fusiform gyri, right premotor cortex, and the intraparietal sulci.
Long Memory in Song Learning by Zebra Finches
Authors: Funabiki Yasuko , Konishi Masakazu
Published: April 2018

Young songbirds use memorized tutor songs as templates to shape their own songs. This process requires control of voice by auditory feedback. We prevented zebra finches from hearing their own vocalizations by exposure to loud noise after 35 d of age, before which they had been reared with song tutors from birth. When the noise stopped at 102-200 d of age, the birds sang unstable and noisy song syllables that did not resemble the tutor syllables. The similarity to the tutor syllables steadily increased until the time of song crystallization ∼30 d later. These findings show that the memory of tutor syllables survives auditory perturbations during the period when it is normally recalled and that zebra finches can use the memory well after the normal period of song development. The temporal order of syllables resembled the tutor model only in birds released from the noise before 80 d of age but not in older birds. Thus, different schedules and processes may govern the learning of syllable phonology and syntax.
Spontaneous Activity of Morphologically Identified Ganglion Cells in the Developing Ferret Retina
Authors: Liets Lauren C. , Olshausen Bruno A. , Wang Guo-Yong , Chalupa Leo M.
Published: April 2018

Whole-cell patch-clamp recordings were made from morphologically identified ganglion cells in the intact retina of developing ferrets. As early as 3 d after birth, all ganglion cells exhibited bursts of spontaneous activity, with the interval between bursts gradually decreasing with maturity. By 2 weeks after birth, ganglion cells could be morphologically differentiated into three major classes (α, β, and γ), and at this time each cell class was characterized by a distinct pattern of spontaneous activity. Dual patch-clamp recordings from pairs of neighboring cells revealed that cells of all morphological classes burst in a coordinated manner, regardless of cell type. These observations suggest that a common mechanism underlies the bursting patterns exhibited by all ganglion cell classes, and that class-specific firing patterns emerge coincident with retinal ganglion cell morphological differentiation.
Corticothalamic Projections from the Rat Primary Somatosensory Cortex
Authors: Killackey Herbert P. , Sherman S. Murray
Published: April 2018

To study the cells of origin of corticothalamic inputs to the ventral posterior and posterior medial nuclei of the somatosensory thalamus in rats, we injected small aliquots of tracer into each nucleus and analyzed the pattern of retrograde labeling in the posteromedial barrel subfield of primary somatosensory cortex, which can be divided into barrel and nonbarrel zones. The ventral posterior nucleus is innervated by neurons in layer VIa of both zones, whereas the posterior medial nucleus is innervated by neurons in layers Vb and VIb of both zones with additional innervation from layer VIa of nonbarrel cortex. Thus, only the posterior medial nucleus receives a layer Vb input. Because the layer Vb input is interpreted as the initiation of a feedforward cortico-thalamocortical pathway, this implies that the target of the posterior medial nucleus, which includes the nonbarrel cortex, is a higher-order cortical area. We thus suggest that this cortical zone, which is classically considered part of the primary somatosensory cortex, should be reclassified as higher-order cortex.
Quantifying Generalization from Trial-by-Trial Behavior of Adaptive Systems that Learn with Basis Functions: Theory and Experiments in Human Motor Control
Authors: Donchin Opher , Francis Joseph T. , Shadmehr Reza
Published: April 2018

During reaching movements, the brain's internal models map desired limb motion into predicted forces. When the forces in the task change, these models adapt. Adaptation is guided by generalization: errors in one movement influence prediction in other types of movement. If the mapping is accomplished with population coding, combining basis elements that encode different regions of movement space, then generalization can reveal the encoding of the basis elements. We present a theory that relates encoding to generalization using trial-by-trial changes in behavior during adaptation. We consider adaptation during reaching movements in various velocity-dependent force fields and quantify how errors generalize across direction. We find that the measurement of error is critical to the theory. A typical assumption in motor control is that error is the difference between a current trajectory and a desired trajectory (DJ) that does not change during adaptation. Under this assumption, in all force fields that we examined, including one in which force randomly changes from trial to trial, we found a bimodal generalization pattern, perhaps reflecting basis elements that encode direction bimodally. If the DJ was allowed to vary, bimodality was reduced or eliminated, but the generalization function accounted for nearly twice as much variance. We suggest, therefore, that basis elements representing the internal model of dynamics are sensitive to limb velocity with bimodal tuning; however, it is also possible that during adaptation the error metric itself adapts, which affects the implied shape of the basis elements.
The Spinal Interneurons and Properties of Glutamatergic Synapses in a Primitive Vertebrate Cutaneous Flexion Reflex
Authors: Li Wen-Chang , Soffe Stephen R. , Roberts Alan
Published: April 2018

Unlike the monosynaptic “stretch” reflex, the exact neuronal pathway for a simple cutaneous reflex has not yet been defined in any vertebrate. In young frog tadpoles, we made whole-cell recordings from pairs of spinal neurons. We found direct, excitatory, glutamatergic synapses from touch-sensitive skin-sensory neurons to sensory pathway interneurons, and then from these sensory interneurons to motoneurons and premotor interneurons on the other side of the body. We conclude that the minimal pathway for this primitive reflex, in which stroking the skin on one side leads to flexion on the other side, is disynaptic. This detailed circuit information has allowed us to ask whether the properties of glutamatergic synapses during the first day of CNS development are tuned to their function in the tadpole's responses. Stroking the skin excites a few sensory neurons. These activate primarily AMPA receptors producing short, strong excitation that activates many sensory pathway interneurons but only allows temporal summation of closely synchronous inputs. In contrast, the excitation produced in contralateral neurons by the sensory pathway interneurons is weak and primarily mediated by NMDA receptors. As a result, considerable summation is required for this excitation to lead to postsynaptic neuron firing and a contralateral flexion. We conclude that from their early functioning, synapses from sensory neurons are strong and those from sensory pathway interneurons are weak. The distribution of glutamate receptors at synapses in this developing circuit is tuned so that synapses have properties suited to their roles in the whole animal's reflex responses.
Illusory Sound Perception in Macaque Monkeys
Authors: Petkov Christopher I. , O'Connor Kevin N. , Sutter Mitchell L.
Published: April 2018

In most natural listening environments, noise occludes objects of interest, and it would be beneficial for an organism to correctly identify those objects. When a sound of interest (“foreground” sound) is interrupted by a loud noise, subjects perceive the entire sound, even if the noise was intense enough to completely mask a part of it. This phenomenon can be exploited to create an illusion: when a silent gap is introduced into the foreground and high-intensity noise is superimposed into the gap, subjects report the foreground as continuing through the noise although that portion of the foreground was deleted. This phenomenon, referred to as auditory induction or amodal completion, is conceptually similar to visual induction, fill-in, illusory motion, and illusory contours. Two rhesus macaque monkeys performed a task designed to assess auditory induction. They were trained to discriminate complete stimuli from those containing a silent gap in the presence of two types of noise. Interrupting noise temporally coincided only with the gap, and in humans this causes induction. Surrounding noise temporally encompassed the entire foreground, and in humans this causes masking without auditory induction. Consistent with previous human psychophysical results, macaques showed better performance with surrounding masking noise than interrupting noise designed to elicit induction. These and other control experiments provide evidence that primates may share a general mechanism to perceptually complete missing sounds.
Dorsal Horn Neurons Firing at High Frequency, But Not Primary Afferents, Release Opioid Peptides that Produce μ-Opioid Receptor Internalization in the Rat Spinal Cord
Authors: Song Bingbing , Marvizón Juan Carlos G.
Published: April 2018

To determine what neural pathways trigger opioid release in the dorsal horn, we stimulated the dorsal root, the dorsal horn, or the dorsolateral funiculus (DLF) in spinal cord slices while superfusing them with peptidase inhibitors to prevent opioid degradation. Internalization of μ-opioid receptors (MOR) and neurokinin 1 receptors (NK1R) was measured to assess opioid and neurokinin release, respectively. Dorsal root stimulation at low, high, or mixed frequencies produced abundant NK1R internalization but no MOR internalization, indicating that primary afferents do not release opioids. Moreover, capsaicin and NMDA also failed to produce MOR internalization. In contrast, dorsal horn stimulation elicited MOR internalization that increased with the frequency, being negligible at <10 Hz and maximal at 500 Hz. The internalization was abolished by the MOR antagonistd-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2(CTAP), in the presence of low Ca2+and by the Na+channel blocker lidocaine, confirming that it was caused by opioid release and neuronal firing. DLF stimulation in “oblique” slices (encompassing the DLF and the dorsal horn of T11-L4) produced MOR internalization, but only in areas near the stimulation site. Moreover, cutting oblique slices across the dorsal horn (but not across the DLF) eliminated MOR internalization in areas distal to the cut, indicating that it was produced by signals traveling in the dorsal horn and not via the DLF. These findings demonstrate that some dorsal horn neurons release opioids when they fire at high frequencies, perhaps by integrating signals from the rostral ventromedial medulla, primary afferents, and other areas of the spinal cord.
Glutamate Receptor Subunit 2 Serine 880 Phosphorylation Modulates Synaptic Transmission and Mediates Plasticity in CA1 Pyramidal Cells
Authors: Seidenman Kenneth J. , Steinberg Jordan P. , Huganir Richard , Malinow Roberto
Published: April 2018

The cytoplasmic C termini of AMPA receptor subunits contain PDZ (postsynaptic density 95/Discs large/zona occludens 1) ligand domains that can control their synaptic trafficking during plasticity. The glutamate receptor subunit 2 (GluR2) PDZ ligand domain can be phosphorylated at serine 880 (S880), and this disrupts interactions with GRIP/ABP (glutamate receptor-interacting protein/AMPA-binding protein) but not with PICK1 (PKC-interacting protein 1). Here, the impact of GluR2 S880 phosphorylation on synaptic transmission and plasticity was explored by expressing, in hippocampal slice cultures, GluR2 subunits containing point mutations that mimic or prevent phosphorylation at this residue. Our results indicate that mimicking GluR2 S880 phosphorylation excludes these receptors from synapses, depresses transmission, and partially occludes long-term depression (LTD). Conversely, mutations that prevent phosphorylation reduce LTD. Disruption of the interaction between GluR2 and GRIP/ABP by S880 phosphorylation may thus facilitate removal of synaptic AMPA receptors and mediate some forms of activity-dependent synaptic depression.
Phonological Grammar Shapes the Auditory Cortex: A Functional Magnetic Resonance Imaging Study
Authors: Jacquemot Charlotte , Pallier Christophe , LeBihan Denis , Dehaene Stanislas , Dupoux Emmanuel
Published: April 2018

Languages differ depending on the set of basic sounds they use (the inventory of consonants and vowels) and on the way in which these sounds can be combined to make up words and phrases (phonological grammar). Previous research has shown that our inventory of consonants and vowels affects the way in which our brains decode foreign sounds (Goto, 1971; Näätänen et al., 1997; Kuhl, 2000). Here, we show that phonological grammar has an equally potent effect. We build on previous research, which shows that stimuli that are phonologically ungrammatical are assimilated to the closest grammatical form in the language (Dupoux et al., 1999). In a cross-linguistic design using French and Japanese participants and a fast event-related functional magnetic resonance imaging (fMRI) paradigm, we show that phonological grammar involves the left superior temporal and the left anterior supramarginal gyri, two regions previously associated with the processing of human vocal sounds.