neuroscience

An amusing YouTube video demonstrates Ivan Pavlov’s principal of classical conditioning with an air gun, a novelty alarm and a reluctant college roommate.

Pavlov discovered that we learn to associate an established response to a new event simply by repeatedly pairing the new event to a situation that already caused the response. Famously he could trigger salivation in a dog just with the sound of a bell, simply by ringing a bell every time food was presented.

This video uses exactly the same principle, but instead of food, an airgun pellet is fired at the roommate causing a painful reaction, and instead of a bell, an annoying novelty alarm is sounded.

Science. Standing on the shoulders of giants.  

Link to YouTube video.

RadioLab has a fantastic mini-edition about the link between our internal thought stream and the development of auditory hallucinations – the experience of ‘hearing voices’.

The programme discusses the theory that the experience of hearing hallucinated ‘voices in your head’ occurs when we lose the ability to recognise our internal thoughts as our own.

Although there is some good evidence that, for example, people diagnosed with schizophrenia who hear voices are less able to recognise their own actions as their own, one crucial aspect not explained by the theory is why many ‘voice hearers’ experience voices with distinct identities.

For example, someone might hear the voice of their dead parent along with someone they knew from childhood where someone else might have discovered the identities of their voices over time, simply from hearing them speak, and they seem to have no relation to specific people they’ve met in their lives.

The programme suggests the idea, which, as far as I know, has never been discussed in the scientific literature, that the identities of the voices could originate from when we learn to internalise voices of people who give us instructions when we’re children – an approach based on the theories of Lev Vygotsky.

It’s a delightful idea, if not a little blue sky, and is accompanied by a brilliant demonstration of the type of study that focuses on hallucinated voices.  

Link to RadioLab ‘Voices in Your Head’ edition.

Psychological Science has a brilliantly conceived study that explains why overhearing someone talk on a mobile phone is so much more annoying than simply overhearing two people in conversation.

It turns out that a one-sided conversation (brilliantly named a ‘half-a-logue’) draws in more of our mental resources because the information is less predictable – like being fed a series of verbal cliff-hangers.

Overheard Cell-Phone Conversations: When Less Speech Is More Distracting.

Psychol Sci. 2010 Sep 3. [Epub ahead of print]

Emberson LL, Lupyan G, Goldstein MH, Spivey MJ.

Why are people more irritated by nearby cell-phone conversations than by conversations between two people who are physically present? Overhearing someone on a cell phone means hearing only half of a conversation-a “halfalogue.” We show that merely overhearing a halfalogue results in decreased performance on cognitive tasks designed to reflect the attentional demands of daily activities. By contrast, overhearing both sides of a cell-phone conversation or a monologue does not result in decreased performance. This may be because the content of a halfalogue is less predictable than both sides of a conversation. In a second experiment, we controlled for differences in acoustic factors between these types of overheard speech, establishing that it is the unpredictable informational content of halfalogues that results in distraction. Thus, we provide a cognitive explanation for why overheard cell-phone conversations are especially irritating: Less-predictable speech results in more distraction for a listener engaged in other tasks.

 

Link to PubMed entry for study.

The development of problems with binge eating commonly occurs after fasting and extreme caloric restriction.  This was demonstrated by a classic experiment during World War II by Ansel Keys.  Conscientious objectors agreed to participate in a study of the effects of extreme calorie restriction.  The research volunteers reported increasing preoccupation with food, dreaming about food, high cravings for food and eventually binge eating when unrestricted food was made available.
Robinson-O'Brien R, Perry CL, Wall MM, Story M, & Neumark-Sztainer D (2009). Adolescent and young adult vegetarianism: better dietary intake and weight outcomes but increased risk of disordered eating behaviors. Journal of the American Dietetic Association, 109 (4), 648-55 PMID: 19328260

Keel PK, & Heatherton TF (2010). Weight suppression predicts maintenance and onset of bulimic syndromes at 10-year follow-up. Journal of abnormal psychology, 119 (2), 268-75 PMID: 20455599

Yates, W. (1992). Weight factors in normal weight bulimia nervosa: A controlled family study International Journal of Eating Disorders, 11 (3), 227-234 DOI: 10.1002/1098-108X(199204)11:33.0.CO;2-X
Boumann CE, & Yates WR (1994). Risk factors for bulimia nervosa: a controlled study of parental psychiatric illness and divorce. Addictive behaviors, 19 (6), 667-75 PMID: 7701977

A Yale University experimental philosopher needs your help – take his online test if you want to find out how your mind works

Mining your brain's fundamental response to cinematic action could make movies more moving

Aggregation of amyloid-β (Aβ) and Tau protein are hallmarks of Alzheimer's disease (AD), and according to the Aβ-cascade hypothesis, Aβ is considered toxic for neurons and Tau a downstream target of Aβ. We have investigated differentiated primary hippocampal neurons for early localized changes following exposure to Aβ oligomers. Initial events become evident by missorting of endogenous Tau into the somatodendritic compartment, in contrast to axonal sorting in normal neurons. In missorted dendritic regions there is a depletion of spines and local increase in Ca²⁺, and breakdown of microtubules. Tau in these regions shows elevated phosphorylation at certain sites diagnostic of AD-Tau (e.g., epitope of antibody 12E8, whose phosphorylation causes detachment of Tau from microtubules, and AT8 epitope), and local elevation of certain kinase activities (e.g., MARK/par-1, BRSK/SADK, p70S6K, cdk5, but not GSK3β, JNK, MAPK). These local effects occur without global changes in Tau, tubulin, or kinase levels. Somatodendritic missorting occurs not only with Tau, but also with other axonal proteins such as neurofilaments, and correlates with pronounced depletion of microtubules and mitochondria. The Aβ-induced effects on microtubule and mitochondria depletion, Tau missorting, and loss of spines are prevented by taxol, indicating that Aβ-induced microtubule destabilization and corresponding traffic defects are key factors in incipient degeneration. By contrast, the rise in Ca²⁺ levels, kinase activities, and Tau phosphorylation cannot be prevented by taxol. Incipient and local changes similar to those of Aβ oligomers can be evoked by cell stressors (e.g., H₂O₂, glutamate, serum deprivation), suggesting some common mechanism of signaling.

Astroglia secrete factors that promote synapse formation and maintenance. In culture, glial contact has also been shown to facilitate synaptogenesis. Here, we examined whether glial contact is important for establishing circuits in vivo by simultaneously monitoring differentiation of glial cells and local synaptogenesis over time. Photoreceptor circuits of the vertebrate retina are particularly suitable for this study because of the relatively simple, laminar organization of their connectivity with their target neurons, horizontal cells and bipolar cells. Also, individual photoreceptor terminals are ensheathed within the outer plexiform layer (OPL) by the processes of one type of glia, Müller glia cells (MGs). We conducted in vivo time-lapse multiphoton imaging of the rapidly developing and relatively transparent zebrafish retina to ascertain the time course of MG development relative to OPL synaptogenesis. The emergence of synaptic triads, indicative of functional photoreceptor circuits, and structural association with glial processes were also examined across ages by electron microscopy. We first show that MG processes form territories that tile within the inner and outer synaptic layers. We then demonstrate that cone photoreceptor synapses are assembled before the elaboration of MG processes in the OPL. Using a targeted cell ablation approach, we also determined whether the maintenance of photoreceptor synapses is perturbed when local MGs are absent. We found that removal of MGs had no appreciable effect on the stability of newly formed cone synapses. Thus, in contrast to other CNS circuits, contact from glia is not necessary for the formation or immediate stabilization of outer retinal synapses.

Degradation of white matter fibers can affect the transmission of signals in brain circuits that normally enable integration of highly lateralized visual and motor processes. Here, we used diffusion tensor imaging tractography in combination with functional magnetic resonance imaging to examine the specific contributions of interhemispheric and intrahemispheric white matter fibers to functional measures of hemispheric transfer and parallel information processing using bilateral and unilateral left and right visual field stimulation in normal and compromised systems. In healthy adults, a greater degree of bilateral processing advantage with the left (nondominant) hand correlated with higher integrity of callosal fibers connecting occipital cortices, whereas less unilateral processing advantage with the right hand correlated with higher integrity of left-hemispheric posterior cingulate fibers. In contrast, alcoholics who have compromised callosal integrity showed less bilateral processing advantage than controls when responding with the left hand and greater unilateral processing advantage when responding with the right hand. We also found degraded left posterior cingulate and posterior callosal fibers in chronic alcoholics, which is consistent with functional imaging results of less left posterior cingulate and extrastriate cortex activation in alcoholics than controls when processing bilateral compared with unilateral visual field stimulation. Together, our results demonstrated that interhemispheric and intrahemispheric white matter fiber pathways mediate visuomotor integration asymmetrically and that subtle white matter fiber degradation in alcoholism attenuated the normal pattern of hemispheric asymmetry, which may have ramifications for the efficiency of visual information processing and fast response execution.

Neurons in layer 4 (L4) of the cortex play an important role in transferring signals from thalamus to other layers of the cortex. Understanding the fundamental properties of synaptic transmission between L4 neurons helps us gain a clear picture of how the neuronal network in L4 cooperates to process sensory information. In the present study, we have determined the underlying parameters that govern synaptic strength, such as quantal size, size of readily releasable vesicle pool, and release probability (Pr) of excitatory synaptic connections within L4 of the visual cortex (V1) and the somatosensory cortex (S1) in mice. Although only a single vesicle is released per release site under physiological conditions at V1 synapses, multivesicular release (MVR) is observed at S1 synapses. In addition, we observed a saturation of postsynaptic receptors at S1 synapses. Other synaptic properties are similar in both cortices. Dynamic clamp experiments suggest that higher Pr and MVR at S1 synapses lower the requirement of the number of synaptic inputs to generate postsynaptic action potentials. In addition, the slower decay of synaptic current and the intrinsic membrane properties of the postsynaptic neuron also contribute to the reliable transmission between S1 neurons.

Prefrontal serotonin 5-HT₂ receptors have been linked to the pathogenesis and treatment of affective disorders, yet their function in psychiatric vulnerability is not known. Here, we examine the effects of 5-HT₂ receptors in a rat model of psychiatric vulnerability using electrophysiology, gene expression, and behavior. Following the early stress of chronic maternal separation, we found that serotonin has atypical 5-HT₂ receptor-mediated excitatory effects in the adult prefrontal cortex that were blocked by the 5-HT_2A receptor antagonist MDL 100907. In the absence of a serotonergic agonist, the intrinsic excitability of the prefrontal cortex was not enhanced relative to controls. Yet, in response to stimulation of 5-HT₂ receptors, adult animals with a history of early stress exhibit heightened prefrontal network activity in vitro, enhanced immediate early gene expression in vivo, and potentiated head shake behavior. These changes arise in the absence of any major alteration of prefrontal 5-HT_2A/C mRNA expression or 5-HT₂ receptor binding. Our microarray results and quantitative PCR validation provide insight into the molecular changes that accompany such enhanced 5-HT₂ receptor function in adult animals following early stress. We observed persistent prefrontal transcriptome changes, with significant enrichment of genes involved in cellular developmental processes, regulation of signal transduction, and G-protein signaling. Specific genes regulated by early stress were validated in an independent cohort, and several altered genes were normalized by chronic blockade of 5-HT₂ receptors in adulthood. Together, our results demonstrate enhanced prefrontal 5-HT₂ receptor function and persistent alterations in prefrontal gene expression in a rat model of psychiatric vulnerability.

We examined the kinetic properties of voltage-gated Na⁺ channels and their contribution to the repetitive spiking activity of medullary raphé neurons, which exhibit slow pacemaking and strong spiking adaptation. The study is based on a combination of whole-cell patch-clamp, modeling and real-time computation. Na⁺ currents were recorded from neurons in brain slices obtained from male and female neonatal rats, using voltage-clamp protocols designed to reduce space-clamp artifacts and to emphasize functionally relevant kinetic features. A detailed kinetic model was formulated to explain the broad range of transient and stationary voltage-dependent properties exhibited by Na⁺ currents. The model was tested by injecting via dynamic clamp a model-based current as a substitute for the native TTX-sensitive Na⁺ currents, which were pharmacologically blocked. The model-based current reproduced well the native spike shape and spiking frequency. The dynamics of Na⁺ channels during repetitive spiking were indirectly examined through this model. By comparing the spiking activities generated with different kinetic models in dynamic-clamp experiments, we determined that state-dependent slow inactivation contributes significantly to spiking adaptation. Through real-time manipulation of the model-based current, we established that suprathreshold Na⁺ current mainly controls spike shape, whereas subthreshold Na⁺ current modulates spiking frequency and contributes to the pacemaking mechanism. Since the model-based current was injected in the soma, the results also suggest that somatic Na⁺ channels are sufficient to establish the essential spiking properties of raphé neurons in vitro.

Proline-rich tyrosine kinase 2 (PYK2), also known as cell adhesion kinase β or protein tyrosine kinase 2b, is a calcium-dependent signaling protein involved in cell migration. Phosphorylation of residue Y402 is associated with activation of PYK2 and leads to the recruitment of downstream signaling molecules. PYK2 was previously implicated in long-term potentiation (LTP); however, the role of PYK2 in long-term depression (LTD) is unknown. Here, we report that PYK2 is activated by NMDA receptor stimulation (chemical LTD) in cultured neurons. Small hairpin RNA-mediated knockdown of PYK2 blocks LTD, but not LTP, in hippocampal slice cultures. We find that the Y402 residue and, to a lesser extent, PYK2 kinase activity contribute to PYK2's role in LTD. Knockdown experiments indicate that PYK2 is required to suppress NMDA-induced extracellular signal-regulated kinase (ERK) phosphorylation. Overexpression of PYK2 depresses NMDA-induced ERK phosphorylation and inhibits LTP, but not LTD. Our data indicate that PYK2 is critical for the induction of LTD, possibly in part by antagonizing ERK signaling in hippocampal neurons.

Processing of complex acoustic scenes depends critically on the temporal integration of sensory information as sounds evolve naturally over time. It has been previously speculated that this process is guided by both innate mechanisms of temporal processing in the auditory system, as well as top-down mechanisms of attention and possibly other schema-based processes. In an effort to unravel the neural underpinnings of these processes and their role in scene analysis, we combine magnetoencephalography (MEG) with behavioral measures in humans in the context of polyrhythmic tone sequences. While maintaining unchanged sensory input, we manipulate subjects' attention to one of two competing rhythmic streams in the same sequence. The results reveal that the neural representation of the attended rhythm is significantly enhanced in both its steady-state power and spatial phase coherence relative to its unattended state, closely correlating with its perceptual detectability for each listener. Interestingly, the data reveal a differential efficiency of rhythmic rates of the order of few hertz during the streaming process, closely following known neural and behavioral measures of temporal modulation sensitivity in the auditory system. These findings establish a direct link between known temporal modulation tuning in the auditory system (particularly at the level of auditory cortex) and the temporal integration of perceptual features in a complex acoustic scene, while mediated by processes of attention.

GABAergic modulation of activity in avian cochlear nucleus neurons has been studied extensively in vitro. However, how this modulation actually influences processing in vivo is not known. We investigated responses of chicken nucleus magnocellularis (NM) neurons to sound while pharmacologically manipulating the inhibitory input from the superior olivary nucleus (SON). SON receives excitatory inputs from nucleus angularis (NA) and nucleus laminaris (NL), and provides GABAergic inputs to NM, NA, NL, and putatively to the contralateral SON. Results from single-unit extracellular recordings from 2 to 4 weeks posthatch chickens show that firing rates of auditory nerve fibers increased monotonically with sound intensity, while that of NM neurons saturated or even decreased at moderate or loud sound levels. Blocking GABAergic input with local application of TTX into the SON induced an increase in firing rate of ipsilateral NM, while that of the contralateral NM decreased at high sound levels. Moreover, local application of bicuculline to NM also increased the firing rate of NM neurons at high sound levels, reduced phase locking, and broadened the frequency-tuning properties of NM neurons. Following application of DNQX, clear evidence of inhibition was observed. Furthermore, the inhibition was tuned to a broader frequency range than the excitatory response areas. We conclude that GABAergic inhibition from SON has at least three physiological influences on the activity of NM neurons: it regulates the firing activity of NM units in a sound-level-dependent manner; it improves phase selectivity; and it sharpens frequency tuning of NM neuronal responses.

Understanding the psychobiological basis of relapse remains a challenge in developing therapies for drug addiction. Relapse in cocaine addiction often occurs following exposure to environmental stimuli previously associated with drug taking. The metabotropic glutamate receptor, mGluR5, is potentially important in this respect; it plays a central role in several forms of striatal synaptic plasticity proposed to underpin associative learning and memory processes that enable drug-paired stimuli to acquire incentive motivational properties and trigger relapse. Using cell type-specific RNA interference, we have generated a novel mouse line with a selective knock-down of mGluR5 in dopamine D1 receptor-expressing neurons. Although mutant mice self-administer cocaine, we show that reinstatement of cocaine-seeking induced by a cocaine-paired stimulus is impaired. By examining different aspects of associative learning in the mutant mice, we identify deficits in specific incentive learning processes that enable a reward-paired stimulus to directly reinforce behavior and to become attractive, thus eliciting approach toward it. Our findings show that glutamate signaling through mGluR5 located on dopamine D1 receptor-expressing neurons is necessary for incentive learning processes that contribute to cue-induced reinstatement of cocaine-seeking and which may underpin relapse in drug addiction.

In the mammalian auditory system, the synapse between efferent olivocochlear (OC) neurons and sensory cochlear hair cells is cholinergic, fast, and inhibitory. This efferent synapse is mediated by the nicotinic 910 receptor coupled to the activation of SK2 Ca²⁺-activated K⁺ channels that hyperpolarize the cell. So far, the ion channels that support and/or modulate neurotransmitter release from the OC terminals remain unknown. To identify these channels, we used an isolated mouse cochlear preparation and monitored transmitter release from the efferent synaptic terminals in inner hair cells (IHCs) voltage clamped in the whole-cell recording configuration. Acetylcholine (ACh) release was evoked by electrically stimulating the efferent fibers that make axosomatic contacts with IHCs before the onset of hearing. Using the specific antagonists for P/Q- and N-type voltage-gated calcium channels (VGCCs), -agatoxin IVA and -conotoxin GVIA, respectively, we show that Ca²⁺ entering through both types of VGCCs support the release process at this synapse. Interestingly, we found that Ca²⁺ entering through the dihydropiridine-sensitive L-type VGCCs exerts a negative control on transmitter release. Moreover, using immunostaining techniques combined with electrophysiology and pharmacology, we show that BK Ca²⁺-activated K⁺ channels are transiently expressed at the OC efferent terminals contacting IHCs and that their activity modulates the release process at this synapse. The effects of dihydropiridines combined with iberiotoxin, a specific BK channel antagonist, strongly suggest that L-type VGCCs negatively regulate the release of ACh by fueling BK channels that are known to curtail the duration of the terminal action potential in several types of neurons.

Contralesional dorsal premotor cortex (cPMd) may support residual motor function following stroke. We performed two complementary experiments to explore how cPMd might perform this role in a group of chronic human stroke patients. First, we used paired-coil transcranial magnetic stimulation (TMS) to establish the physiological influence of cPMd on ipsilesional primary motor cortex (iM1) at rest. We found that this influence became less inhibitory/more facilitatory in patients with greater clinical impairment. Second, we applied TMS over cPMd during functional magnetic resonance imaging (fMRI) in these patients to examine the causal influence of cPMd TMS on the whole network of surviving cortical motor areas in either hemisphere and whether these influences changed during affected hand movement. We confirmed that hand grip-related activation in cPMd was greater in more impaired patients. Furthermore, the peak ipsilesional sensorimotor cortex activity shifted posteriorly in more impaired patients. Critical new findings were that concurrent TMS-fMRI results correlated with the level of both clinical impairment and neurophysiological impairment (i.e., less inhibitory/more facilitatory cPMd-iM1 measure at rest as assessed with paired-coil TMS). Specifically, greater clinical and neurophysiological impairment was associated with a stronger facilitatory influence of cPMd TMS on blood oxygenation level-dependent signal in posterior parts of ipsilesional sensorimotor cortex during hand grip, corresponding to the posteriorly shifted sensorimotor activity seen in more impaired patients. cPMd TMS was not found to influence activity in other brain regions in either hemisphere. This state-dependent influence on ipsilesional sensorimotor regions may provide a mechanism by which cPMd supports recovered function after stroke.

Mutations in ubiquitously expressed metabolic genes often lead to CNS-specific effects, presumably because of the high metabolic demands of neurons. However, mutations in omnipresent metabolic pathways can conceivably also result in cell type-specific effects because of cell-specific requirements for intermediate products. One such example is the zebrafish noir mutant, which we found to be mutated in the pdhb gene, coding for the E1 β subunit of the pyruvate dehydrogenase complex. This vision mutant is described as blind and was isolated because of its vision defect-related darker appearance. A detailed morphological, behavioral, and physiological analysis of the phenotype revealed an unexpected specific effect on the retina. Surprisingly, the cholinergic amacrine cells of the inner retina are affected earlier than the photoreceptors. This might be attributable to the inability of these cells to maintain production of their neurotransmitter acetylcholine. This is reflected in an earlier loss of motion vision, followed only later by a general loss of light perception. Since both characteristics of the phenotype are attributable to a loss of acetyl-CoA production by pyruvate dehydrogenase, we used a ketogenic diet to bypass this metabolic block and could indeed partially rescue vision and prolong survival of the larvae. The noir mutant provides a case for a systemic disease with ocular manifestation with a surprising specific effect on the retina given the ubiquitous requirement for the mutated gene.

The initiation of axonal filopodia is the first step in the formation of collateral branches and synaptic structures. In sensory neurons, nerve growth factor (NGF) promotes the formation of axonal filopodia and branches. However, the signaling and cytoskeletal mechanisms of NGF-induced initiation of axonal filopodia are not clear. Axonal filopodia arise from precursor axonal cytoskeletal structures termed filamentous actin (F-actin) patches. Patches form spontaneously and are transient. Although filopodia emerge from patches, only a fraction of patches normally gives rise to filopodia. Using chicken sensory neurons and live imaging of enhanced yellow fluorescent protein (eYFP)–actin dynamics, we report that NGF promotes the formation of axonal filopodia by increasing the rate of F-actin patch formation but not the fraction of patches that give rise to filopodia. We also demonstrate that activation of the phosphatidylinositol 3-kinase (PI3K)–Akt pathway is sufficient and required for driving the formation of axonal F-actin patches, filopodia, and axon branches. Using the green fluorescent protein–plekstrin homology domain of Akt, which targets to PI3K-generated phosphatidylinositol-3,4,5-triphosphate (PIP₃), we report localized microdomains of PIP₃ accumulation that form in synchrony with F-actin patches and that NGF promotes the formation of microdomains of PIP₃ and patches. Finally, we find that, in NGF, F-actin patches form in association with axonal mitochondria and oxidative phosphorylation is required for patch formation. This investigation demonstrates that surprisingly NGF promotes formation of axonal filopodia by increasing the formation of cytoskeletal filopodial precursors (patches) through localized microdomains of PI3K signaling but not the emergence of filopodia from patches.