Hot off the presses! Feb 10 Neuron

The Feb 10 issue of the Neuron is now up on Pubget (About Neuron): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Decision Making: Singin' in the Brain
  - Neuron (Cambridge Mass ) 69(3):399-401 (2011)
  Which neurons in the brain "decide" to initiate particular behaviors in response to sensory information? In this issue of Neuron, two papers (Kohatsu et al. and von Philipsborn et al.) identify candidates in the courtship circuitry of Drosophila. The activity of these neurons is both regulated by sex pheromones and necessary and sufficient to trigger male love song.
• Synaptotagmin 4: A New Antiobesity Target?
  - Neuron (Cambridge Mass ) 69(3):401-403 (2011)
  In this issue of Neuron, Zhang et al. show that Synaptotagmin 4 (Syt4) is specifically induced in adult hypothalamic oxytocin neurons by high-fat diet. Evidence is provided to support a critical role for Syt4 in negative regulation of oxytocin release, which in turn is responsible for diet-induced obesity, raising the possibility of using Syt4 as a new antiobesity target.
• Decision Time for Free Will
  - Neuron (Cambridge Mass ) 69(3):404-406 (2011)
  In this issue of Neuron, Fried et al. report electrical recordings from single neurons in several areas of the human medial frontal lobe prior to voluntary movement. These data shed important new light on the neuronal mechanisms of human volition and on the hotly debated relation between consciousness and will.
• Sensorimotor Integration in Speech Processing: Computational Basis and Neural Organization
  - Neuron (Cambridge Mass ) 69(3):407-422 (2011)
  Sensorimotor integration is an active domain of speech research and is characterized by two main ideas, that the auditory system is critically involved in speech production and that the motor system is critically involved in speech perception. Despite the complementarity of these ideas, there is little crosstalk between these literatures. We propose an integrative model of the speech-related "dorsal stream" in which sensorimotor interaction primarily supports speech production, in the form of a state feedback control architecture. A critical component of this control system is forward sensory prediction, which affords a natural mechanism for limited motor influence on perception, as recent perceptual research has suggested. Evidence shows that this influence is modulatory but not necessary for speech perception. The neuroanatomy of the proposed circuit is discussed as well as some probable clinical correlates including conduction aphasia, stuttering, and aspects of! schizophrenia.
• Huntington's Disease: Can Mice Lead the Way to Treatment?
  - Neuron (Cambridge Mass ) 69(3):423-435 (2011)
  Mouse models for Huntington's Disease (HD) and HD patients demonstrate motor and behavioral dysfunctions, such as progressive loss of coordination and memory, and share similar transcriptional profiles and striatal neuron atrophy. Clear differences between the mouse and human diseases include almost complete striatal degeneration and rarity of intranuclear inclusions in HD, and the fact that mice expressing full-length mutant huntingtin do not demonstrate a shortened life span characteritstic of HD. While no clinical interventions tested in mouse models to date have delayed disease progression, the mouse models provide an invaluable tool for both investigating the underlying pathogenic processes and developing new effective therapies. Inherent differences between humans and mice must be considered in the search for efficacious treatments for HD, but the striking similarities between human HD and mouse models support the view that these models are a biologically relevan! t system to support the identification and testing of potential clinical therapies.
• Activity-Induced Notch Signaling in Neurons Requires Arc/Arg3.1 and Is Essential for Synaptic Plasticity in Hippocampal Networks
  - Neuron (Cambridge Mass ) 69(3):437-444 (2011)
  Notch signaling in the nervous system has been most studied in the context of cell fate specification. However, numerous studies have suggested that Notch also regulates neuronal morphology, synaptic plasticity, learning, and memory. Here we show that Notch1 and its ligand Jagged1 are present at the synapse, and that Notch signaling in neurons occurs in response to synaptic activity. In addition, neuronal Notch signaling is positively regulated by Arc/Arg3.1, an activity-induced gene required for synaptic plasticity. In Arc/Arg3.1 mutant neurons, the proteolytic activation of Notch1 is disrupted both in vivo and in vitro. Conditional deletion of Notch1 in the postnatal hippocampus disrupted both long-term potentiation (LTP) and long-term depression (LTD), and led to deficits in learning and short-term memory. Thus, Notch signaling is dynamically regulated in response to neuronal activity, Arc/Arg3.1 is a context-dependent Notch regulator, and Notch1 is required for the! synaptic plasticity that contributes to memory formation.
• Habenula "Cholinergic" Neurons Corelease Glutamate and Acetylcholine and Activate Postsynaptic Neurons via Distinct Transmission Modes
  - Neuron (Cambridge Mass ) 69(3):445-452 (2011)
  Acetylcholine is an important neurotransmitter, and the habenulo-interpeduncular projection is a major cholinergic pathway in the brain. To study the physiological properties of cholinergic transmission in the interpeduncular nucleus (IPN), we used a transgenic mouse line in which the light-gated cation channel ChannelRhodopsin-2 is selectively expressed in cholinergic neurons. Cholinergic axonal terminals were activated by light pulses, and postsynaptic responses were recorded from IPN neurons. Surprisingly, brief photostimulation produces fast excitatory postsynaptic currents that are mediated by ionotropic glutamate receptors, suggesting wired transmission of glutamate. By contrast, tetanic photostimulation generates slow inward currents that are largely mediated by nicotinic acetylcholine receptors, suggesting volume transmission of acetylcholine. Finally, vesicular transporters for glutamate and acetylcholine are coexpressed on the same axonal terminals in the IPN! . These results strongly suggest that adult brain "cholinergic" neurons can corelease glutamate and acetylcholine, but these two neurotransmitters activate postsynaptic neurons via different transmission modes.
• Early Functional Impairment of Sensory-Motor Connectivity in a Mouse Model of Spinal Muscular Atrophy
  - Neuron (Cambridge Mass ) 69(3):453-467 (2011)
  To define alterations of neuronal connectivity that occur during motor neuron degeneration, we characterized the function and structure of spinal circuitry in spinal muscular atrophy (SMA) model mice. SMA motor neurons show reduced proprioceptive reflexes that correlate with decreased number and function of synapses on motor neuron somata and proximal dendrites. These abnormalities occur at an early stage of disease in motor neurons innervating proximal hindlimb muscles and medial motor neurons innervating axial muscles, but only at end-stage disease in motor neurons innervating distal hindlimb muscles. Motor neuron loss follows afferent synapse loss with the same temporal and topographical pattern. Trichostatin A, which improves motor behavior and survival of SMA mice, partially restores spinal reflexes, illustrating the reversibility of these synaptic defects. Deafferentation of motor neurons is an early event in SMA and may be a primary cause of motor dysfunction th! at is amenable to therapeutic intervention.
• DSL-Notch Signaling in the Drosophila Brain in Response to Olfactory Stimulation
  - Neuron (Cambridge Mass ) 69(3):468-481 (2011)
  Delta/Serrate/Lag2 (DSL) ligands and their Notch family receptors have profound and pervasive roles in development. They are also expressed in adult tissues, notably in mature neurons and glia in the brain, where their roles are unknown. Here, focusing on the sense of smell in adult Drosophila, we show that Notch is activated in select olfactory receptor neurons (ORNs) in an odorant-specific fashion. This response requires olfactory receptor activity and the Notch ligand Delta. We present evidence that Notch activation depends on synaptic transmission by the ORNs in which the receptors are active and is modulated by the activity of local interneurons in the antennal lobe. It is also subject to regulatory inputs from olfactory receptor activity in other ORNs. These findings identify a correlate of stimulus-dependent brain activity and potentially new forms of neural integration and plasticity.
• Reelin Regulates Cadherin Function via Dab1/Rap1 to Control Neuronal Migration and Lamination in the Neocortex
  - Neuron (Cambridge Mass ) 69(3):482-497 (2011)
  Neuronal migration is critical for establishing neocortical cell layers and migration defects can cause neurological and psychiatric diseases. Recent studies show that radially migrating neocortical neurons use glia-dependent and glia-independent modes of migration, but the signaling pathways that control different migration modes and the transitions between them are poorly defined. Here, we show that Dab1, an essential component of the reelin pathway, is required in radially migrating neurons for glia-independent somal translocation, but not for glia-guided locomotion. During migration, Dab1 acts in translocating neurons to stabilize their leading processes in a Rap1-dependent manner. Rap1, in turn, controls cadherin function to regulate somal translocation. Furthermore, cell-autonomous neuronal deficits in somal translocation are sufficient to cause severe neocortical lamination defects. Thus, we define the cellular mechanism of reelin function during radial migratio! n, elucidate the molecular pathway downstream of Dab1 during somal translocation, and establish the importance of glia-independent motility in neocortical development.
• Female Contact Activates Male-Specific Interneurons that Trigger Stereotypic Courtship Behavior in Drosophila
  - Neuron (Cambridge Mass ) 69(3):498-508 (2011)
  We determined the cellular substrate for male courtship behavior by quasinatural and artificial stimulation of brain neurons. Activation of fruitless (fru)-expressing neurons via stimulation of thermosensitive dTrpA1 channels induced an entire series of courtship acts in male Drosophila placed alone without any courting target. By reducing the number of neurons expressing dTrpA1 by MARCM, we demonstrated that the initiation of courtship behavior is significantly correlated with the activation of the transmidline P1 interneurons, the descending P2b interneurons, or both, indicating that these interneurons trigger courtship. Using an experimental paradigm in which a tethered male can be stimulated to initiate courtship by touching his foreleg tarsus to a female's abdomen, we found that P1 neurites of tethered males showed a transient Ca2+ rise after tarsal stimulation with the female-associated sensory cues. These observations strongly suggest that P1 neurons are the pri! me components of the neural circuitry that initiates male courtship.
• Neuronal Control of Drosophila Courtship Song
  - Neuron (Cambridge Mass ) 69(3):509-522 (2011)
  The courtship song of the Drosophila male serves as a genetically tractable model for the investigation of the neural mechanisms of decision-making, action selection, and motor pattern generation. Singing has been causally linked to the activity of the set of neurons that express the sex-specific fru transcripts, but the specific neurons involved have not been identified. Here we identify five distinct classes of fru neuron that trigger or compose the song. Our data suggest that P1 and pIP10 neurons in the brain mediate the decision to sing, and to act upon this decision, while the thoracic neurons dPR1, vPR6, and vMS11 are components of a central pattern generator that times and shapes the song's pulses. These neurons are potentially connected in a functional circuit, with the descending pIP10 neuron linking the brain and thoracic song centers. Sexual dimorphisms in each of these neurons may explain why only males sing.
• Neuropeptide Exocytosis Involving Synaptotagmin-4 and Oxytocin in Hypothalamic Programming of Body Weight and Energy Balance
  - Neuron (Cambridge Mass ) 69(3):523-535 (2011)
  Hypothalamic neuropeptides play essential roles in regulating energy and body weight balance. Energy imbalance and obesity have been linked to hypothalamic signaling defects in regulating neuropeptide genes; however, it is unknown whether dysregulation of neuropeptide exocytosis could be critically involved. This study discovered that synaptotagmin-4, an atypical modulator of synaptic exocytosis, is expressed most abundantly in oxytocin neurons of the hypothalamus. Synaptotagmin-4 negatively regulates oxytocin exocytosis, and dietary obesity is associated with increased vesicle binding of synaptotagmin-4 and thus enhanced negative regulation of oxytocin release. Overexpressing synaptotagmin-4 in hypothalamic oxytocin neurons and centrally antagonizing oxytocin in mice are similarly obesogenic. Synaptotagmin-4 inhibition prevents against dietary obesity by normalizing oxytocin release and energy balance under chronic nutritional excess. In conclusion, the negative regul! ation of synaptotagmin-4 on oxytocin release represents a hypothalamic basis of neuropeptide exocytosis in controlling obesity and related diseases.
• Neural Mechanisms of Tactile Motion Integration in Somatosensory Cortex
  - Neuron (Cambridge Mass ) 69(3):536-547 (2011)
  How are local motion signals integrated to form a global motion percept? We investigate the neural mechanisms of tactile motion integration by presenting tactile gratings and plaids to the fingertips of monkeys, using the tactile analogue of a visual monitor and recording the responses evoked in somatosensory cortical neurons. The perceived directions of the gratings and plaids are measured in parallel psychophysical experiments. We identify a population of somatosensory neurons that exhibit integration properties comparable to those induced by analogous visual stimuli in area MT and find that these neural responses account for the perceived direction of the stimuli across all stimulus conditions tested. The preferred direction of the neurons and the perceived direction of the stimuli can be predicted from the weighted average of the directions of the individual stimulus features, highlighting that the somatosensory system implements a vector average mechanism to compu! te tactile motion direction that bears striking similarities to its visual counterpart.
• Internally Generated Preactivation of Single Neurons in Human Medial Frontal Cortex Predicts Volition
  - Neuron (Cambridge Mass ) 69(3):548-562 (2011)
  Understanding how self-initiated behavior is encoded by neuronal circuits in the human brain remains elusive. We recorded the activity of 1019 neurons while twelve subjects performed self-initiated finger movement. We report progressive neuronal recruitment over 1500 ms before subjects report making the decision to move. We observed progressive increase or decrease in neuronal firing rate, particularly in the supplementary motor area (SMA), as the reported time of decision was approached. A population of 256 SMA neurons is sufficient to predict in single trials the impending decision to move with accuracy greater than 80% already 700 ms prior to subjects' awareness. Furthermore, we predict, with a precision of a few hundred ms, the actual time point of this voluntary decision to move. We implement a computational model whereby volition emerges once a change in internally generated firing rate of neuronal assemblies crosses a threshold. Video Abstract To view the video inline, enable JavaScript on your browser. However, you can download and view the video by clicking on the icon below Download this Video (58511 K)
• Fear-Conditioning Mechanisms Associated with Trait Vulnerability to Anxiety in Humans
  - Neuron (Cambridge Mass ) 69(3):563-571 (2011)
  Investigations of fear conditioning in rodents and humans have illuminated the neural mechanisms underlying cued and contextual fear. A critical question is how personality dimensions such as trait anxiety act through these mechanisms to confer vulnerability to anxiety disorders, and whether humans' ability to overcome acquired fears depends on regulatory skills not characterized in animal models. In a neuroimaging study of fear conditioning in humans, we found evidence for two independent dimensions of neurocognitive function associated with trait vulnerability to anxiety. The first entailed increased amygdala responsivity to phasic fear cues. The second involved impoverished ventral prefrontal cortical (vPFC) recruitment to downregulate both cued and contextual fear prior to omission (extinction) of the aversive unconditioned stimulus. These two dimensions may contribute to symptomatology differences across anxiety disorders; the amygdala mechanism affecting the deve! lopment of phobic fear and the frontal mechanism influencing the maintenance of both specific fears and generalized anxiety.
• Neuronal Dynamics Underlying High- and Low-Frequency EEG Oscillations Contribute Independently to the Human BOLD Signal
  - Neuron (Cambridge Mass ) 69(3):572-583 (2011)
  Work on animals indicates that BOLD is preferentially sensitive to local field potentials, and that it correlates most strongly with gamma band neuronal synchronization. Here we investigate how the BOLD signal in humans performing a cognitive task is related to neuronal synchronization across different frequency bands. We simultaneously recorded EEG and BOLD while subjects engaged in a visual attention task known to induce sustained changes in neuronal synchronization across a wide range of frequencies. Trial-by-trial BOLD fluctuations correlated positively with trial-by-trial fluctuations in high-EEG gamma power (60–80 Hz) and negatively with alpha and beta power. Gamma power on the one hand, and alpha and beta power on the other hand, independently contributed to explaining BOLD variance. These results indicate that the BOLD-gamma coupling observed in animals can be extrapolated to humans performing a task and that neuronal dynamics underlying high- and low-frequen! cy synchronization contribute independently to the BOLD signal.