bluuebunny/crossref_metadata_2025 huggingface dataset:
Developmental Changes in Eye-Blink Conditioning and Neuronal Activity in the Cerebellar Interpositus Nucleus
Authors: Freeman John H. , Nicholson Daniel A.
Published: April 2018

Neuronal activity was recorded in the cerebellar interpositus nucleus in infant rats during classical conditioning of the eye-blink response. The percentage and amplitude of eye-blink conditioned responses increased as a function of postnatal age. Learning-specific neuronal activity in the cerebellum emerged ontogenetically in parallel with the eye-blink conditioned response. There were also age-specific changes in neuronal activity after the onset of the conditioned and unconditioned stimuli. The results indicate that the development of the eye-blink conditioned response may depend on the development of stimulus-evoked neuronal responses and learning-specific plasticity in the cerebellum. Functional immaturity in the afferent neural pathways may limit the induction of neural plasticity in the cerebellum and thereby limit the development of the eye-blink conditioned response.
Nerve Growth Factor (NGF) Augments Cortical and Hippocampal Cholinergic Functioning after p75NGF Receptor-Mediated Deafferentation But Impairs Inhibitory Avoidance and Induces Fear-Related Behaviors
Authors: Winkler Jürgen , Ramirez Gilbert A. , Thal Leon J. , Waite Jerene J.
Published: April 2018

Nerve growth factor (NGF) enhances cholinergic functioning in animals with a compromised cholinergic basal forebrain (CBF). Immunotoxic lesions targeting low-affinity NGF receptor (p75NGF receptor)-bearing CBF neurons provide a selective model for testing the effects of NGF on residual cholinergic neurons. Rats received PBS or the immunotoxin 192IgG-saporin (192Sap) intracerebroventricularly at two doses (1 or 2.7 μg) known to produce different degrees of cholinergic deficit. Seven weeks after lesioning, half of each group received either NGF or cytochromecintracerebroventricularly for 7 weeks. The two doses of 192Sap produced 50 and 80% depletions of choline acetyltransferase (ChAT) activity in the neocortex and hippocampus. NGF produced the greatest increase in ChAT activity in controls, intermediate in low-lesioned, and smallest in highly lesioned animals. NGF-treated animals showed reduced weight gain, hyper-responsiveness to acoustic stimuli, and decreased inhibitory avoidance. Although general motor behavior was affected by neither 192Sap nor NGF in an open field task, highly lesioned rats took longer to reach the platform during water maze testing. Impaired spatial orientation in finding a hidden platform at the previously acquired position was mitigated by NGF. Hypertrophic changes of residual CBF neurons, Schwann cell hyperplasia, and aberrant axonal sprouting around the medulla were observed in NGF-treated animals only, independent of the preexisting lesion. Our results indicate that NGF has a limited capacity to enhance functioning of residual CBF neurons. More importantly, NGF augmented fear-related behaviors and adverse neuroproliferative changes that may restrict its therapeutic use.
Comparison of the Laminar Distribution of Input from Areas 17 and 18 of the Visual Cortex to the Lateral Geniculate Nucleus of the Cat
Authors: Murphy P. C. , Duckett S. G. , Sillito A. M.
Published: April 2018

The feedback from area 18 of the cat visual cortex to the lateral geniculate nucleus has been investigated by labeling and reconstructing seventeen axons of known receptive field position and eye preference. The distribution of boutons from each axon was quantified with respect to the compartments of the geniculate complex, and the results were compared with an equivalent analysis of fourteen area 17 axons. Area 18 axons form large, sparse arborizations that extend up to 1.9 mm laterally (1170 ± 85 μm; mean ± SEM), with a core of relatively dense innervation spanning on average 600 ± 70 μm (mean ± SEM). Thus, they have the potential to influence the transmission of visual information from well beyond their own classical receptive fields. In this respect, they are surprisingly similar to the axons from area 17, despite the fact that the two cortical areas have very different retinotopy. However, there are important differences between the pathways. Area 18 axons project more heavily to the C layers and medial interlaminar nucleus. Whereas the input from both areas to the A layers is biased toward the layer appropriate to the eye preference of each axon, the area 18 input to magnocellular layer C is not. The distribution of area 18 boutons favors the bottom of their preferred A layer, and the area 17 boutons favor the top. These differences mirror those seen in the afferent pathways, suggesting that each cortical area preferentially targets the cells from which it receives input. Finally, their greater diameter suggests that area 18 axons provide the earliest feedback signal in the corticogeniculate loop.
Breeding Conditions Induce Rapid and Sequential Growth in Adult Avian Song Control Circuits: A Model of Seasonal Plasticity in the Brain
Authors: Tramontin Anthony D. , Hartman Vesta N. , Brenowitz Eliot A.
Published: April 2018

In adult songbirds, seasonal changes in photoperiod and circulating testosterone (T) stimulate structural changes within the neural song control circuitry. The mechanisms that control this natural plasticity are poorly understood. To determine how quickly and in what sequence the song nuclei respond to changing daylength and circulating T, we captured 18 adult male white-crowned sparrows and kept them on short days for 12 weeks. We killed five of these birds and exposed the rest to long days (LD) and elevated T. We killed these birds either 7 or 20 d after LD + T exposure. We measured song nuclei volumes and cellular attributes, the mass of the vocal production organ (the syrinx), and song behavior. The neostriatal song control nucleus HVC (also known as “high vocal center”), added 50,000 neurons and increased in size within 7 d of exposure to LD + T. Efferent targets of HVC, the robust nucleus of the archistriatum (RA), and area X of the parolfactory lobe grew more slowly and were not significantly larger until day 20 of the study. The tracheosyringeal portion of the hypoglossal nucleus (nXIIts), which receives projections from RA and normally grows in response to seasonal cues, did not grow over the time course of this study. Syringeal mass increased within 7 d of LD + T treatment. The anatomical changes in the brain were accompanied by behavioral changes in song production. On day 7 when the song circuitry was incompletely developed, male sparrows sang less stereotyped songs than males at day 20 with more completely developed song circuits. These results suggest that the song circuitry responds rapidly and sequentially to breeding-typical conditions (long days and elevated T), and that song stereotypy increases as nuclei within this circuitry grow.
Abnormal Auditory Experience Induces Frequency-Specific Adjustments in Unit Tuning for Binaural Localization Cues in the Optic Tectum of Juvenile Owls
Authors: Gold Joshua I. , Knudsen Eric I.
Published: April 2018

Early auditory experience shapes the auditory spatial tuning of neurons in the barn owl's optic tectum in a frequency-dependent manner. We examined the basis for this adaptive plasticity in terms of changes in tuning for frequency-specific interaural time differences (ITDs) and level differences (ILDs), the dominant sound localization cues. We characterized broadband and narrowband ITD and ILD tuning in normal owls and in owls raised with an acoustic filtering device in one ear that caused frequency-dependent changes in sound timing and level. In normal owls, units were tuned to frequency-specific ITD and ILD values that matched those produced by sound sources located in their visual receptive fields. In contrast, in device-reared owls, ITD tuning at most sites was shifted from normal by ∼55 μsec toward open-ear leading for 4 kHz stimuli and 15 μsec toward the opposite-ear leading for 8 kHz stimuli, reflecting the acoustic effects of the device. ILD tuning was shifted in the adaptive direction by ∼3 dB for 4 kHz stimuli and 8 dB for 8 kHz stimuli, but these shifts were substantially smaller than expected based on the acoustic effects of the device. Most sites also exhibited conspicuously abnormal frequency–response functions, including a strong dependence on stimulus ITD and a reduction of normally robust responses to 6 kHz stimuli. The results demonstrate that the response properties of high-order auditory neurons in the optic tectum are adjusted during development to reflect the influence of frequency-specific features of the binaural localization cues experienced by the individual.
Neural Systems Underlying the Recognition of Familiar and Newly Learned Faces
Authors: Leveroni Catherine L. , Seidenberg Michael , Mayer Andrew R. , Mead Larissa A. , Binder Jeffrey R. , Rao Stephen M.
Published: April 2018

Memory for famous faces can be used to examine the neural systems underlying retrieval from long-term memory. To date, there have been a limited number of functional neuroimaging investigations examining famous face recognition. In this study, we compared recognition of famous faces to recognition of newly learned faces. Whole-brain, event-related functional magnetic resonance imaging was used to image regional changes in neural activity in 11 subjects during the encoding of unfamiliar faces and during familiarity judgments for: (1) newly learned faces, (2) unfamiliar face distractors, and (3) famous faces. Image analyses were restricted to correct recognition trials. Recognition accuracy and response time to famous and recently learned faces were equivalent. Recognition of famous faces was associated with a widespread network of bilateral brain activations involving the prefrontal, lateral temporal, and mesial temporal (hippocampal and parahippocampal regions) regions compared to recognition of recently encoded faces or unfamiliar faces seen for the first time. Findings are discussed in relation to current proposals concerning the neural regions thought to participate in long-term memory retrieval and, more specifically, in relation to retrieval of information from the person identity semantic system.
Coexpression of Cloned α1B, β2a, and α2/δ Subunits Produces Non-Inactivating Calcium Currents Similar to Those Found in Bovine Chromaffin Cells
Authors: Cahill Anne L. , Hurley Joyce H. , Fox Aaron P.
Published: April 2018

Chromaffin cells express N-type calcium channels identified on the basis of their high sensitivity to block by ω-conotoxin GVIA (ω-CgTx GVIA). In contrast to neuronal N-type calcium currents that inactivate during long depolarizations and that require negative holding potentials to remove inactivation, many chromaffin cells exhibit N-type calcium channel currents that show little inactivation during maintained depolarizations and that exhibit no decrease in channel availability at depolarized holding potentials. N-type calcium channels are thought to be produced by combination of the pore-forming α1Bsubunit and accessory β and α2/δ subunits. To examine the molecular composition of the non-inactivating N-type calcium channel, we cloned the α1Band accessory β (β1b, β1c,β2a, β2b, and β3a) subunits found in bovine chromaffin cells. Expression of the subunits in eitherXenopusoocytes or human embryonic kidney 293 cells produced high-threshold calcium currents that were blocked by ω-CgTx GVIA. Coexpression of bovine α1Bwith β1b, β1c, β2b,or β3aproduced currents that were holding potential dependent. In contrast, coexpression of bovine α1Bwith β2aproduced holding potential-independent calcium currents that closely mimicked native non-inactivating currents, suggesting that non-inactivating N-type channels consist of bovine α1B, α2/δ, and β2a.
Estrogen-Induced Activation of the Mitogen-Activated Protein Kinase Cascade in the Cerebral Cortex of Estrogen Receptor-α Knock-Out Mice
Authors: Singh Meharvan , Sétáló György , Guan Xiaoping , Frail Donald E. , Toran-Allerand C. Dominique
Published: April 2018

We have shown previously in the developing cerebral cortex that estrogen elicits the rapid and sustained activation of multiple signaling proteins within the mitogen-activated protein (MAP) kinase cascade, including B-Raf and extracellular signal-regulated kinase (ERK). Using estrogen receptor (ER)-α gene-disrupted (ERKO) mice, we addressed the role of ER-α in mediating this action of estrogen in the brain. 17β-Estradiol increased B-Raf activity and MEK (MAP kinase/ERK kinase)-dependent ERK phosphorylation in cerebral cortical explants derived from both ERKO and their wild-type littermates. The ERK response was stronger in ERKO-derived cultures but, unlike that of wild-type cultures, was not blocked by the estrogen receptor antagonist ICI 182,780. Surprisingly, both the ER-α selective ligand 16α-iodo-17β-estradiol and the ER-β selective ligand genistein failed to elicit ERK phosphorylation, suggesting that a different mechanism or receptor may mediate estrogen-induced ERK phosphorylation in the cerebral cortex. Interestingly, the transcriptionally inactive stereoisomer 17α-estradiol did elicit a strong induction of ERK phosphorylation, which, together with the inability of the ER-α- and ER-β-selective ligands to elicit ERK phosphorylation, and of ICI 182,780 to block the actions of estradiol in ERKO cultures, supports the hypothesis that a novel, estradiol-sensitive and ICI-insensitive estrogen receptor may mediate 17β-estradiol-induced activation of ERK in the brain.
dCLOCK Is Present in Limiting Amounts and Likely Mediates Daily Interactions between the dCLOCK–CYC Transcription Factor and the PER–TIM Complex
Authors: Bae Kiho , Lee Choogon , Hardin Paul E. , Edery Isaac
Published: April 2018

InDrosophila melanogasterfour circadian clock proteins termed PERIOD (PER), TIMELESS (TIM), dCLOCK (dCLK), and CYCLE (CYC/dBMAL1) function in a transcriptional feedback loop that is a core element of the oscillator mechanism. dCLK and CYC are members of the basic helix-loop-helix (bHLH)/PAS (PER-ARNT-SIM) superfamily of transcription factors and are required for high-level expression ofperandtimand repression ofdClk, whereas PER and TIM inhibit dCLK–CYC-mediated transcription and lead to the activation ofdClk. To understand further the dynamic regulation within the circadian oscillator mechanism, we biochemically characterizedin vivo-produced CYC, determined the interactions of the four clock proteins, and calculated their absolute levels as a function of time. Our results indicate that throughout a daily cycle the majority of the dCLK present in adult heads stably interacts with CYC, indicating that CYC is the primaryin vivopartner of dCLK. dCLK–CYC dimers are bound by PER and TIM during the late evening and early morning, suggesting the formation of a tetrameric complex with impaired transcriptional activity. Although dCLK is present in limiting amounts and CYC is by far the most abundant of the four clock proteins that have been examined, PER and TIM appear to interact preferentially with dCLK. Our results suggest that dCLK is the main component regulating the daily abundance of transcriptionally active dCLK–CYC complexes.
NMDA Receptor-Mediated Subthreshold Ca2+Signals in Spines of Hippocampal Neurons
Authors: Kovalchuk Yury , Eilers Jens , Lisman John , Konnerth Arthur
Published: April 2018

We have used rapid confocal microscopy to investigate the mechanism of Ca2+signals in individual dendritic spines of hippocampal CA1 pyramidal cells. The experiments focused on the signals that occur during single weak synaptic responses that were subthreshold for triggering postsynaptic action potentials. These Ca2+signals were not strongly affected by blocking the EPSPs with the AMPA receptor antagonist CNQX. The signals were also not strongly reduced by blocking T-type voltage-gated Ca2+channels (VGCCs) with Ni2+or by blocking a broad range of VGCCs with intracellular D890. The spine Ca2+signals were blocked by NMDA receptor channel (NMDAR) antagonist and had the voltage dependence characteristic of these channels. Neither ryanodine nor cyclopiazonic acid (CPA), substances known to deplete intracellular Ca2+stores, substantially reduced the amplitude of synaptically evoked Ca2+signals. CPA slowed the recovery phase of Ca2+signals in spines produced by synaptic stimulation or by backpropagating action potentials, suggesting a role of intracellular stores in Ca2+reuptake. Thus, we find that Ca2+release from intracellular stores is not required to produce spine Ca2+signals. We conclude that synaptic Ca2+signals in spines are primarily caused by Ca2+entry through NMDARs. Although these channels are largely blocked by Mg2+at voltages near the resting potential, they can nevertheless produce significant Ca2+elevation. The resulting Ca2+signals are an integral component of individual evoked or spontaneous synaptic events and may be important in the maintenance of synaptic function.
Imaging Extracellular Waves of Glutamate during Calcium Signaling in Cultured Astrocytes
Authors: Innocenti Barbara , Parpura Vladimir , Haydon Philip G.
Published: April 2018

A growing body of evidence proposes that glial cells have the potential to play a role as modulators of neuronal activity and synaptic transmission by releasing the neurotransmitter glutamate (Araque et al., 1999). We explore the spatial nature of glutamate release from astrocytes with an enzyme-linked assay system and CCD imaging technology. In the presence of glutamate,l-glutamic dehydrogenase (GDH) reduces NAD+to NADH, a product that fluoresces when excited with UV light. Theoretically, provided that GDH and NAD+are present in the bathing saline, the release of glutamate from stimulated astrocytes can be optically detected by monitoring the accumulation of NADH. Indeed, stimuli that induce a wave of elevated calcium among astrocytes produced a corresponding spread of extracellular NADH fluorescence. Treatment of cultures either with thapsigargin, to deplete internal calcium stores, or with the membrane-permeant calcium chelator BAPTA AM significantly decreased the accumulation of NADH, demonstrating that this fluorometric assay effectively monitors calcium-dependent glutamate release. With a temporal resolution of 500 msec and spatial resolution of ∼20 μm, discrete regions of glutamate release were not reliably resolved. The wave of glutamate release that underlies the NADH fluorescence propagated at an average speed of ∼26 μm/sec, correlating with the rate of calcium wave progression (10–30 μm/sec), and caused a localized accumulation of glutamate in the range of 1–100 μm. Further analysis of the fluorescence accumulation clearly demonstrated that glutamate is released in a regenerative manner, with subsequent cells that are involved in the calcium wave releasing additional glutamate.
Activation of Extracellular Signal-Regulated Protein Kinases Is Associated with a Sensitized Locomotor Response to D2Dopamine Receptor Stimulation in Unilateral 6-Hydroxydopamine-Lesioned Rats
Authors: Cai Guoping , Zhen Xuechu , Uryu Kunihiro , Friedman Eitan
Published: April 2018

Evidence indicates that mitogen-activated protein kinase (MAPK) pathways play a crucial role in the neurobiology of the nervous system. In the present study, dopamine receptor-mediated regulation of extracellular signal-regulated kinases (ERKs) was examined in rats in which the nigrostriatal dopaminergic pathway was unilaterally lesioned by 6-hydroxydopamine (6-OHDA). Subcutaneous injections of the D2receptor agonist quinpirole significantly increased tyrosine-phosphorylated ERK1/2 in lesioned striatum, whereas the D1receptor agonist SKF38393 failed to activate ERKs. Quinpirole-induced phosphorylation of ERK1/2 was seen as early as 3 min and peaked at 15 min after the challenge. In parallel, striatal ERK kinase activity, measured by thein vitrokinase assay, was increased 2.5-fold on the lesioned side after the administration of quinpirole. Immunohistochemical examination of brain sections after quinpirole administration revealed significant increases in ERK1/2 immunostaining in perinuclear and intranuclear areas of striatal neurons. This increase was much more pronounced on the lesioned than the intact side. Furthermore, quinpirole-induced contralateral rotation was decreased by 48.7 and 50.7%, respectively, when the striatal ERK pathway was selectively inhibited by a single intrastriatal injection of the MAPK/ERK kinase inhibitor PD098059 or after a continuous 7 d intrastriatal infusion of ERK1/2 antisense oligodeoxynucleotide. The results demonstrate, for the first time, that the ERK signaling pathway is activated in denervated striatum in response to stimulation of D2dopamine receptors and that the resulting imbalance in striatal ERK activity contributes, at least in part, to neuronal plasticity that underlies D2dopamine receptor-mediated contralateral rotation in unilateral 6-OHDA denervated rats.
Afferent Regulation of Inhibitory Synaptic Transmission in the Developing Auditory Midbrain
Authors: Vale Carmen , Sanes Dan H.
Published: April 2018

To determine whether afferent innervation regulates the strength of inhibitory connections in the gerbil auditory midbrain, both cochleas were surgically removed in postnatal day 7 animals, before sound-driven activity is first observed. Inhibitory synaptic currents were measured in a brain slice preparation 1–7 d after the ablations. Whole-cell and gramicidin-perforated patch recordings were obtained from inferior colliculus neurons, and IPSCs were evoked by stimulation of the commissure of the inferior colliculus (CIC) or the ipsilateral lateral lemniscus (LL) in the presence of kynurenic acid. Deafferentation led to a 24 mV depolarizing shift in the IPSC equilibrium potential within 1 d of deafferentation. As a consequence, there was a large reduction of IPSC amplitude at a holding potential of −20 mV in neurons from bilaterally ablated animals. Furthermore, both afferent pathways displayed a 50% reduction of the inhibitory synaptic conductance after deafferentation, indicating that driving force was not solely responsible for the decline in IPSC amplitude. When paired pulses were delivered to the LL or CIC pathway in control neurons, the evoked IPSCs exhibited facilitation. However, paired pulse facilitation was nearly eliminated after deafferentation. Thus, normal innervation affects inhibitory synaptic strength by regulating postsynaptic chloride homeostasis and presynaptic transmitter release properties.
Conscious and Unconscious Processing of Nonverbal Predictability in Wernicke's Area
Authors: Bischoff-Grethe Amanda , Proper Shawnette M. , Mao Hui , Daniels Karen A. , Berns Gregory S.
Published: April 2018

The association of nonverbal predictability and brain activation was examined using functional magnetic resonance imaging in humans. Participants regarded four squares displayed horizontally across a screen and counted the incidence of a particular color. A repeating spatial sequence with varying levels of predictability was embedded within a random color presentation. Both Wernicke's area and its right homolog displayed a negative correlation with temporal predictability, and this effect was independent of individuals' conscious awareness of the sequence. When individuals were made aware of the underlying sequential predictability, a widespread network of cortical regions displayed activity that correlated with the predictability. Conscious processing of predictability resulted in a positive correlation to activity in right prefrontal cortex but a negative correlation in posterior parietal cortex. These results suggest that conscious processing of predictability invokes a large-scale cortical network, but independently of awareness, Wernicke's area processes predictive events in time and may not be exclusively associated with language.
A Proprioceptive Role for an Exteroceptive Mechanoafferent Neuron inAplysia
Authors: Borovikov Dmitry , Evans Colin G. , Jing Jian , Rosen Steven C. , Cropper Elizabeth C.
Published: April 2018

Afferent regulation of centrally generated activity is likely to be more complex than has been established. We show that a neuron that is an exteroceptor can also function as a proprioceptor. We study theAplysianeuron B21. Previous data suggest that B21 functions as an exteroceptor during the radula closing/retraction phase of ingestive feeding. We show that the tissue innervated by B21, the subradula tissue (SRT), is innervated by a motor neuron (B66) and that B66-induced SRT contractions trigger centripetal spikes in B21. Thus, B21 is also a proprioceptor. To determine whether exteroceptive and proprioceptive activities occur during the same phase of ingestive feeding, we further characterize B66. We show that B66 stimulation does not close or retract the radula. Instead it opens it. Moreover, B66 is electrically coupled to other opening/protraction neurons. Finally, we elicit motor programs in semi-intact preparations and show that during radula opening/protraction we observe B66 activity, SRT contractions, and spikes in B21 that can be eliminated if B66 is indirectly hyperpolarized. B21 is, therefore, likely to act as an exteroceptor during one phase of ingestive feeding and as a proprioceptor during the antagonistic phase. Previous experiments have shown that centripetal spikes in B21 are only transmitted to one follower if they are “gated in” by depolarization. During ingestive programs B21 is centrally depolarized during closing/retraction, but it is not depolarized during opening/protraction. We sought to determine whether there are other followers that receive B21 input when it is not centrally depolarized. We found one such cell. Moreover, we found that stimulation of B21 during radula opening/protraction significantly decreases the duration of this phase of behavior. Thus, proprioceptive activity in B21 is likely to have an impact on motor programs.
Long-Lasting Depolarizations in Mitral Cells of the Rat Olfactory Bulb
Authors: Carlson Greg C. , Shipley Michael T. , Keller Asaf
Published: April 2018

We investigated the mechanisms of long-lasting depolarizing potentials (LLDs) generated in mitral cells with whole-cell patch recordings in the rat olfactory bulb slice. LLDs occur spontaneously and are evoked by either orthodromic stimulation of the olfactory nerve or antidromic stimulation of mitral and tufted (M/T) cells. LLDs are followed by a long refractory period, limiting LLD generation to ∼1 Hz. LLD production does not appear to involve either intrinsic voltage-activated or metabotropic mechanisms. The initiation of LLDs requires activation of non-NMDA but not NMDA receptors. Dual recordings from the apical dendrites and somata of mitral cells show that LLDs are generated in the distal portion of the apical dendrite, most likely in the glomerulus. The rising phase of LLDs shows characteristics of polyneuronal input, including a high variability and sensitivity to charge screening. Paired recordings from adjacent mitral cells suggest that LLDs occur synchronously only in cells whose apical dendrites ramify in the same glomerulus. These findings suggest that LLDs involve recurrent, intraglomerular dendrodendritic interactions among M/T cells.
Hypothalamic–Pituitary–Adrenal Dysfunction inApoe−/−Mice: Possible Role in Behavioral and Metabolic Alterations
Authors: Raber Jacob , Akana Susan F. , Bhatnagar Seema , Dallman Mary F. , Wong Derek , Mucke Lennart
Published: April 2018

Several neurological diseases are frequently accompanied by dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis. The HPA axis regulates the secretion of glucocorticoids (GCs), which play important roles in diverse brain functions, including cognition, emotion, and feeding. Under physiological conditions, GCs are adaptive and beneficial; however, prolonged elevations in GC levels may contribute to neurodegeneration and brain dysfunction. In the current study, we demonstrate that apolipoprotein E (apoE) deficiency results in age-dependent dysregulation of the HPA axis through a mechanism affecting primarily the adrenal gland.Apoe−/−mice, which develop neurodegenerative alterations as they age, had an age-dependent increase in basal adrenal corticosterone content and abnormally increased plasma corticosterone levels after restraint stress, whereas their plasma and pituitary adrenocorticotropin levels were either unchanged or lower than those in controls. HPA axis dysregulation was associated with behavioral and metabolic alterations. When anxiety levels were assessed in the elevated plus maze,Apoe−/−mice showed more anxiety than wild-type controls.Apoe−/−mice also showed reduced activity in the open field. Finally,Apoe−/−mice showed age-dependent increases in food and water intake, stomach and body weights, and decreases in brown and white adipose tissues. These results support a key role for apoE in the tonic inhibition of steroidogenesis and HPA axis activity and have important implications for the behavioral analysis ofApoe−/−mice.
Hippocampal Abnormalities and Enhanced Excitability in a Murine Model of Human Lissencephaly
Authors: Fleck Mark W. , Hirotsune Shinji , Gambello Michael J. , Phillips-Tansey Emily , Suares Gregory , Mervis Ronald F. , Wynshaw-Boris Anthony , McBain Chris J.
Published: April 2018

Human cortical heterotopia and neuronal migration disorders result in epilepsy; however, the precise mechanisms remain elusive. Here we demonstrate severe neuronal dysplasia and heterotopia throughout the granule cell and pyramidal cell layers of mice containing a heterozygous deletion ofLis1, a mouse model of human 17p13.3-linked lissencephaly. Birth-dating analysis using bromodeoxyuridine revealed that neurons inLis1+/−murine hippocampus are born at the appropriate time but fail in migration to form a defined cell layer. Heterotopic pyramidal neurons inLis1+/−mice were stunted and possessed fewer dendritic branches, whereas dentate granule cells were hypertrophic and formed spiny basilar dendrites from which the principal axon emerged. Both somatostatin- and parvalbumin-containing inhibitory neurons were heterotopic and displaced into both stratum radiatum and stratum lacunosum-moleculare. Mechanisms of synaptic transmission were severely disrupted, revealing hyperexcitability at Schaffer collateral–CA1 synapses and depression of mossy fiber–CA3 transmission. In addition, the dynamic range of frequency-dependent facilitation ofLis1+/−mossy fiber transmission was less than that of wild type. Consequently,Lis1+/−hippocampi are prone to interictal electrographic seizure activity in an elevated [K+]omodel of epilepsy. InLis1+/−hippocampus, intense interictal bursting was observed on elevation of extracellular potassium to 6.5 mm, a condition that resulted in only minimal bursting in wild type. These anatomical and physiological hippocampal defects may provide a neuronal basis for seizures associated with lissencephaly.
Enhancement of the Dense-Core Vesicle Secretory Cycle by Glucocorticoid Differentiation of PC12 Cells: Characteristics of Rapid Exocytosis and Endocytosis
Authors: Elhamdani Abdeladim , Brown Mary E. , Artalejo Cristina R. , Palfrey H. Clive
Published: April 2018

The secretory cycle of dense-core vesicles (DCVs) in physiologically stimulated patch-clamped PC12 cells was analyzed using both amperometry and capacitance measurements. Untreated cells had low or undetectable Ca currents and sparse secretory responses to short depolarizations. Dexamethasone (5 μm) treatment for 5–7 d tripled Ca current magnitude and dramatically increased quantal secretion in response to depolarization with action potentials. Such cells expressed L-, N-, and P-type Ca channels, and depolarization evoked rapid catecholamine secretion recorded as amperometric spikes; the average latency was ∼50 msec. These spikes were much smaller and shorter than those of primary adrenal chromaffin cells, reflecting the smaller size of DCVs in PC12 cells. Depolarizing pulse trains also elicited a rapid increase in membrane capacitance corresponding to exocytosis in differentiated but not in naı̈ve cells. On termination of stimulation, membrane capacitance declined within 20 sec to baseline indicative of rapid endocytosis (RE). RE did not take place when secretion was stimulated in the presence of Ba or Sr, indicating that RE is Ca-specific. RE was blocked when either anti-dynamin antibodies or the pleckstrin homology domain of dynamin-1 was loaded into the cell via the patch pipette. These studies indicate that neuroendocrine differentiation of PC12 cells with glucocorticoids enhances the development of the excitable membrane and increases the coupling between Ca channels and vesicle release sites, leading to rapid exocytosis and endocytosis. Slow catecholamine secretion in undifferentiated cells may be caused in part by a lack of localized secretory machinery rather than being an intrinsic property of dense-core vesicles.
NMDA Receptor Content of Synapses in Stratum Radiatum of the Hippocampal CA1 Area
Authors: Racca Claudia , Stephenson F. Anne , Streit Peter , Roberts J. David B. , Somogyi Peter
Published: April 2018

Glutamate receptors activated by NMDA (NMDARs) or AMPA (AMPARs) are clustered on dendritic spines of pyramidal cells. Both the AMPAR-mediated postsynaptic responses and the synaptic AMPAR immunoreactivity show a large intersynapse variability. Postsynaptic responses mediated by NMDARs show less variability. To assess the variability in NMDAR content and the extent of their coexistence with AMPARs in Schaffer collateral–commissural synapses of adult rat CA1 pyramidal cells, electron microscopic immunogold localization of receptors has been used. Immunoreactivity of NMDARs was detected in virtually all synapses on spines, but AMPARs were undetectable, on average, in 12% of synapses. A proportion of synapses had a very high AMPAR content relative to the mean content, resulting in a distribution more skewed toward larger values than that of NMDARs. The variability of synaptic NMDAR content [coefficient of variation (CV), 0.64–0.70] was much lower than that of the AMPAR content (CV, 1.17–1.45). Unlike the AMPAR content, the NMDAR content showed only a weak correlation with synapse size. As reported previously for AMPARs, the immunoreactivity of NMDARs was also associated with the spine apparatus within spines. The results demonstrate that the majority of the synapses made by CA3 pyramidal cells onto spines of CA1 pyramids express both NMDARs and AMPARs, but with variable ratios. A less-variable NMDAR content is accompanied by a wide variability of AMPAR content, indicating that the regulation of expression of the two receptors is not closely linked. These findings support reports that fast excitatory transmission at some of these synapses is mediated by activation mainly of NMDARs.
Elevated Levels of the Chemokine GRO-1 Correlate with Elevated Oligodendrocyte Progenitor Proliferation in theJimpyMutant
Authors: Wu Qian , Miller Robert H. , Ransohoff Richard M. , Robinson Shenandoah , Bu Jie , Nishiyama Akiko
Published: April 2018

The dysmyelinating mutantjimpy(jp) arises from a point mutation in the mouse gene encoding proteolipid protein and is characterized by severe dysmyelination attributable to oligodendrocyte death. This mutant was used to investigate the regulation of oligodendrocyte progenitor proliferation in the postnatal spinal cord. At postnatal day 18,jpspinal cord contained a three- to eightfold greater number of proliferating oligodendrocyte progenitor cells than didwild-type(wt) spinal cord. Increased proliferation injpspinal cord was accompanied by a twofold increase in the number of progenitor cells. Semiquantitative reverse transcriptase-PCR revealed no change in the level of mRNA encoding the platelet-derived growth factor A, transforming growth factor-β, or insulin-like growth factor-I, all of which have been implicated as regulators of proliferation and differentiation of oligodendrocyte progenitor cells. There was, however, a 17-fold increase in the level of mRNA encoding the chemokine GRO-1 and a 5- to 6-fold increase in GRO-1 protein in thejpspinal cord. Double immunofluorescence labeling revealed elevated levels of GRO-1 in reactive astrocytes injpspinal cord white matter.In vitrostudies indicated that extracts fromjpspinal cord stimulated oligodendrocyte progenitor proliferation. Furthermore, removal of GRO-1 fromjpextracts by immunoprecipitation reduced the proliferation of progenitor cells to a level similar to that achieved bywtextracts. These findings suggest a novel mechanism by which proliferation of oligodendrocyte progenitor cells is regulated in the postnatal spinal cord in response to insult.
Emx2Is Required for Growth of the Hippocampus But Not for Hippocampal Field Specification
Authors: Tole Shubha , Goudreau Guy , Assimacopoulos Stavroula , Grove Elizabeth A.
Published: April 2018

The vertebrateEmxgenes are expressed in a nested pattern in early embryonic cerebral cortex, such that a medial strip of cortex expressesEmx2but notEmx1. This pattern suggests thatEmxgenes could play a role in specifying different areas or fields of the cortex along the mediolateral axis. Such a role has been supported by the observation that in mice lacking functionalEmx2the hippocampus is shrunken and the most medial field of the cortex, the hippocampal dentate gyrus, appears by cytoarchitecture to be missing (Pellegrini et al., 1996; Yoshida et al., 1997). Use of region-specific molecular markers shows, however, that hippocampal fields are specified and correctly positioned in theEmx2mutant. In particular, a dentate cell population is generated, although it fails to form a morphological gyrus. This failure may be part of a more widespread medial cortical defect in the mutant. Examination of cortical cell proliferation and differentiation indicates a disruption of the maturation of the medial cortex in the absence ofEmx2.Thus,Emx2is required for normal growth and maturation of the hippocampus but not for the specification of cells to particular hippocampal field identities.
Impaired Preference Conditioning after Anterior Temporal Lobe Resection in Humans
Authors: Johnsrude Ingrid S. , Owen Adrian M. , White Norman M. , Zhao W. Vivienne , Bohbot Veronique
Published: April 2018

Research with animals suggests that structures within the amygdaloid nuclear complex (ANC) are critical for acquiring associations between rewarding events and neutral stimuli, a form of conditioning often manifested in a subsequent preference for those (conditioned) stimuli. In this study, we investigated the relationship between the ANC and preference learning in humans. Three abstract monochrome patterns were presented to each subject over 180 trials in the context of a counting task requiring working memory. One pattern was paired with food reward on 90% of the trials in which it was presented and with no food reward on the other 10% of trials. The other patterns were similarly reinforced, but at ratios of 50:50% and 10:90% with reward and nonreward, respectively. Subsequently, a group of 21 normal participants preferred the pattern paired most often with reward to that paired least often with reward, and they did not explicitly relate their preferences to the conditioning procedure, but instead attributed them to the characteristics of the patterns themselves. Unlike the normal controls, a group of patients with unilateral surgical lesions that included the ANC (15 left, 18 right) did not show conditioned preferences, but performed normally on a measure of working memory. In contrast, 13 patients with unilateral damage confined to frontal cortex exhibited normal conditioned preferences but were impaired on the working memory task. This double dissociation provides clear evidence that, in humans as in other animals, reward-related learning (conditioned reward) critically depends on a circuit involving inferotemporal cortex and the ANC.
What and When: Parallel and Convergent Processing in Motor Control
Authors: Sakai Katsuyuki , Hikosaka Okihide , Takino Ryousuke , Miyauchi Satoru , Nielsen Matthew , Tamada Tomoe
Published: April 2018

Successful motor behavior requires making appropriate response (response selection) at the right time (timing adjustment). Earlier psychological studies have suggested that the response selection and timing adjustment processes are performed serially in separate stages. We tested this hypothesis using functional magnetic resonance imaging. The subjects performed a choice reaction time task in four conditions: two (on-line response selection required or not) by two (on-line timing adjustment required or not). We found that the neural correlates for the two processes were indeed separate: the anterior medial premotor cortex (presupplementary motor area) was selectively active in response selection, whereas the cerebellar posterior lobe was selectively active in timing adjustment. However, the functional separation was only partial in that the lateral premotor cortex and the intraparietal sulcus were active equally for response selection and timing adjustment. The lateral premotor cortex was most active when both processes were required, suggesting that it integrates the information on response selection and the information on timing adjustment; alternatively, it might contribute to the allocation of attentional resources during dual information processing. The intraparietal sulcus was equally active when either response selection or timing adjustment was required, suggesting that it modifies, rather than integrates, these processes. Furthermore, our results suggest that these activations related to response selection and timing adjustment were distinct from sensory or motor processes.
Neuronal Correlates of Fear in the Lateral Amygdala: Multiple Extracellular Recordings in Conscious Cats
Authors: Paré Denis , Collins Dawn R.
Published: April 2018

Much data implicates the amygdala in the expression and learning of fear. Yet, few studies have examined the neuronal correlates of fear in the amygdala. This study aimed to determine whether fear is correlated to particular activity patterns in the lateral amygdaloid (LA) nucleus. Cats, chronically implanted with multiple microelectrodes in the LA and a catheter in the femoral artery, learned that a series of tones interrupted by a period of silence (5 sec) preceded the administration of a footshock. During the silent period, their blood pressure increased, indicating that they anticipated the noxious stimulus. In parallel, the firing rate of LA neurons doubled, and the discharges of simultaneously recorded cells became more synchronized. Moreover, cross-correlation of focal LA waves revealed a significant increase in synchrony restricted to the theta band. In keeping with this, perievent histograms of neuronal discharges revealed rhythmic changes in the firing probability of LA neurons in relation to focal theta waves. Finally, the responsiveness of LA cells to the stimuli predicting the footshock (the tones) increased during the trials, whereas responses to unrelated stimuli (perirhinal shocks) remained stable. Thus, during the anticipation of noxious stimuli, a state here defined anthropomorphically as fear, the firing rate of LA neurons increases, and their discharges become more synchronized through a modulation at the theta frequency. The presence of theta oscillations in the LA might facilitate cooperative interactions between the amygdala and cortical areas involved in memory.
Fos Imaging Reveals Differential Patterns of Hippocampal and Parahippocampal Subfield Activation in Rats in Response to Different Spatial Memory Tests
Authors: Vann Seralynne D. , Brown Malcolm W. , Erichsen Jonathan T. , Aggleton John P.
Published: April 2018

We compared neuronal activation, as measured by Fos staining, during different spatial tasks in two experiments. The counts of Fos-stained neurons in the hippocampus increased as the spatial demands of the tasks increased, the tasks having been carefully matched for other factors. In Experiment 1, matched groups of rats either ran a standard eight-arm radial maze task or were trained to run up and down just one arm of the maze; the number of runs and rewards was identical in both conditions. In Experiment 2, rats were trained on the eight-arm maze but in different rooms. On the critical test day, both groups were run in the same room so that one group now performed with novel landmarks. All hippocampal subfields (dentate gyrus, CA3, CA1, dorsal, ventral, and caudal subiculum) showed a relative increases in c-fosactivation in the eight-arm (Experiment 1) and novel room (Experiment 2) conditions, the sole exception being the ventral subiculum in Experiment 2. Although increased c-fosactivation was found in both dorsal and ventral hippocampus, in Experiment 2 the relative increase was significantly greater in the dorsal hippocampus. Parahippocampal cortices responded heterogeneously: the perirhinal cortex failed to show increased activation in both experiments, in contrast to the entorhinal and postrhinal cortices. Subsequent comparisons confirmed that the perirhinal and postrhinal cortices responded in qualitatively different ways, the perirhinal cortex differing from the rest of the hippocampal formation. These experiments, which provide the first analysis of hippocampal Fos production during tests of allocentric spatial working memory, reveal that all components of the hippocampus are activated, but that under certain conditions the dorsal hippocampus is disproportionately involved.
The Extracellular Signal-Regulated Kinase Cascade Is Required for NMDA Receptor-Independent LTP in Area CA1 But Not Area CA3 of the Hippocampus
Authors: Kanterewicz Beatriz I. , Urban Nathan N. , McMahon David B. T. , Norman Eric D. , Giffen Laura J. , Favata Margaret F. , Scherle Peggy A. , Trzăskos James M. , Barrionuevo German , Klann Eric
Published: April 2018

Activation of extracellular signal-regulated kinase (ERK) has been shown to be necessary for NMDA receptor-dependent long-term potentiation (LTP). We studied the role of ERK in three forms of NMDA receptor-independent LTP: LTP induced by very high-frequency stimulation (200 Hz-LTP), LTP induced by the K+channel blocker tetraethylammonium (TEA) (TEA-LTP), and mossy fiber (MF) LTP (MF-LTP). We found that ERK was activated in area CA1 after the induction of both 200 Hz-LTP and TEA-LTP and that this activation required the influx of Ca2+through voltage-gated Ca2+channels. Inhibition of the ERK signaling cascade with either PD 098059 or U0126 prevented the induction of both 200 Hz-LTP and TEA-LTP in area CA1. In contrast, neither PD 098059 nor U0126 prevented MF-LTP in area CA3 induced by either brief or long trains of high-frequency stimulation. U0126 also did not prevent forskolin-induced potentiation in area CA3. However, incubation of slices with forskolin, an activator of the cAMP-dependent protein kinase (PKA) cascade, did result in increases in active ERK and cAMP response element-binding protein (CREB) phosphorylation in area CA3. The forskolin-induced increase in active ERK was inhibited by U0126, whereas the increase in CREB phosphorylation was not, which suggests that in area CA3 the PKA cascade is not coupled to CREB phosphorylation via ERK. Overall, our observations indicate that activation of the ERK signaling cascade is necessary for NMDA receptor-independent LTP in area CA1 but not in area CA3 and suggest a divergence in the signaling cascades underlying NMDA receptor-independent LTP in these hippocampal subregions.