Axonal signals in the assembly of neural circuitry

Recent work in Drosophila and rodents has revealed that proteins transported along axons and delivered to pathway and target cell populations play important roles in the construction of neural circuitry. Interestingly, the parallels between these systems may extend to the identities of some of the molecules involved.     

Optogenetic manipulation of neural circuitry in vivo

Recent advances in optogenetics have permitted investigations of specific cell types in the nervous system with unprecedented precision and control. This review will discuss the use of optogenetic techniques in the study of mammalian neural circuitry in vivo, as well as practical and theoretical considerations in their application.     

Lumping and splitting the neural circuitry of visual attention

Shifts of gaze and of covert attention rely on tightly linked yet divergent neural mechanisms. In this issue of Neuron, Gregoriou et?al. (2012) provide interesting evidence that different functional classes of neurons within the frontal eye field contribute uniquely to these two functions.     

Regulation of KLF4 by posttranslational modification circuitry in endocrine resistance

KLF4 plays an important role in orchestrating a variety of cellular events, including cell-fate decision, genome stability and apoptosis. Its deregulation is correlated with human diseases such as breast cancer and gastrointestinal cancer. Results from recent biochemical studies have revealed that KLF4 is tightly regulated by posttranslational modifications. Here we report a new finding that KLF4 orchestrates estrogen receptor signaling and facilitates endocrine resistance. We also uncovered the underlying mechanism that alteration of KLF4 by posttranslational modifications such as phosphorylation and ubiquitylation changes tumor cell response to endocrine therapy drugs. IHC analyses using based on human breast cancer specimens showed the accumulation of KLF4 protein in ER-positive breast cancer tissues. Elevated KLF4 expression significantly correlated with prognosis and endocrine resistance. Our drug screening for suppressing KLF4 protein expression led to identification of Src kinase to be a critical player in modulating KLF4-mediated tamoxifen resistance. Depletion of VHL (von Hippel-Lindau tumor suppressor), a ubiquitin E3 ligase for KLF4, reduces tumor cell sensitivity to tamoxifen. We demonstrated phosphorylation of VHL by Src enhances proteolysis of VHL that in turn leads to upregulation of KLF4 and increases endocrine resistance. Suppression of Src-VHL-KLF4 cascade by Src inhibitor or enhancement of VHL-KLF4 ubiquitination by TAT-KLF4 (371-420AAa) peptides re-sensitizes tamoxifen-resistant breast cancer cells to tamoxifen treatment. Taken together, our findings demonstrate a novel role for KLF4 in modulating endocrine resistance via the Src-VHL-KLF4 axis.     

Orphanin FQ/nociceptin: from neural circuitry to behavior

Orphanin FQ/nociceptin (OFQ/N), the endogenous ligand for the "orphan" opioid receptor ORL-1 (NOP(1)) was first identified in 1995. In the years since its discovery, a large body of evidence has accumulated showing that OFQ/N and its receptor are widely distributed in the nervous system, and showing that OFQ/N has potent and indiscriminate inhibitory actions on neurons in many regions. However, numerous studies investigating the functional role of OFQ/N in physiology or behavior have failed to provide a coherent view. Pain and analgesia have been the best studied, and administration of OFQ/N is reported to have no effect, to produce hyperalgesia, analgesia or anti-hyperalgesia. Effects of OFQ/N receptor antagonists have proved similarly contentious. In an attempt to resolve this controversy, we investigated the actions of OFQ/N on the activity of physiologically characterized neurons in the rostral ventromedial medulla, a region with a well-documented role in pain modulation(Heinricher et al., 1997). The results of those experiments demonstrate that this peptide is neither "anti-opioid" or "anti-hyperalgesic". It is simply inhibitory. For this reason, the effects seen in functional studies will only be fully understood when examined in the context of identified neural circuits.     

Memory and addiction: shared neural circuitry and molecular mechanisms

An important conceptual advance in the past decade has been the understanding that the process of drug addiction shares striking commonalities with neural plasticity associated with natural reward learning and memory. Basic mechanisms involving dopamine, glutamate, and their intracellular and genomic targets have been the focus of attention in this research area. These two neurotransmitter systems, widely distributed in many regions of cortex, limbic system, and basal ganglia, appear to play a key integrative role in motivation, learning, and memory, thus modulating adaptive behavior. However, many drugs of abuse exert their primary effects precisely on these pathways and are able to induce enduring cellular alterations in motivational networks, thus leading to maladaptive behaviors. Current theories and research on this topic are reviewed from an integrative systems perspective, with special emphasis on cellular, molecular, and behavioral aspects of dopamine D-1 and glutamate NMDA signaling, instrumental learning, and drug cue conditioning.     

Regulation of afferent transmission in the feeding circuitry of Aplysia

Although feeding in Aplysia is mediated by a central pattern generator (CPG), the activity of this CPG is modified by afferent input. To determine how afferent activity produces the widespread changes in motor programs that are necessary if behavior is to be modified, we have studied two classes of feeding sensory neurons. We have shown that afferent-induced changes in activity are widespread because sensory neurons make a number of synaptic connections. For example, sensory neurons make monosynaptic excitatory connections with feeding motor neurons. Sensori-motor transmission is, however, regulated so that changes in the periphery do not disrupt ongoing activity. This results from the fact that sensory neurons are also electrically coupled to feeding interneurons. During motor programs sensory neurons are, therefore, rhythmically depolarized via central input. These changes in membrane potential profoundly affect sensori-motor transmission. For example, changes in membrane potential alter spike propagation in sensory neurons so that spikes are only actively transmitted to particular output regions when it is behaviorally appropriate. To summarize, afferent activity alters motor output because sensory neurons make direct contact with motor neurons. Sensori-motor transmission is, however, centrally regulated so that changes in the periphery alter motor programs in a phase-dependent manner.     

Identifying the neural circuitry of alcohol craving and relapse vulnerability

With no further intervention, relapse rates in detoxified alcoholics are high and usually exceed 80% of all detoxified patients. It has been suggested that stress and exposure to priming doses of alcohol and to alcohol-associated stimuli (cues) contribute to the relapse risk after detoxification. This article focuses on neuronal correlates of cue responses in detoxified alcoholics. Current brain imaging studies indicate that dysfunction of dopaminergic, glutamatergic and opioidergic neurotransmission in the brain reward system (ventral striatum including the nucleus accumbens) can be associated with alcohol craving and functional brain activation in neuronal systems that process attentional relevant stimuli, reward expectancy and experience. Increased functional brain activation elicited by such alcohol-associated cues predicted an increased relapse risk, whereas high brain activity elicited by affectively positive stimuli may represent a protective factor and was correlated with a decreased prospective relapse risk. These findings are discussed with respect to psychotherapeutic and pharmacological treatment options.     

Regulation of trunk myogenesis by the neural crest: a new facet of neural crest-somite interactions

It is well established that the somitic mesoderm regulates early stages of neural crest development and further segmentation of crest-derived peripheral ganglia. The possibility that neural crest progenitors feed back on the somites was, however, not explored. Two recent studies provide evidence that the neural crest regulates somite-derived myogenesis by distinct mechanisms.     

Central neural circuitry in the jellyfish Aglantha: a model 'simple nervous system'

Like other hydrozoan medusae, Aglantha lacks a brain, but the two marginal nerve rings function together as a central nervous system. Twelve neuronal and two excitable epithelial conduction systems are described and their interactions summarized. Aglantha differs from most medusae in having giant axons. It can swim and contract its tentacles in two distinct ways (escape and slow). Escape responses are mediated primarily by giant axons but conventional interneurons are also involved in transmission of information within the nerve rings during one form of escape behavior. Surprisingly, giant axons provide the motor pathway to the swim muscles in both escape and slow swimming. This is possible because these axons can conduct calcium spikes as well as sodium spikes and do so on an either/or basis without overlap. The synaptic and ionic bases for these responses are reviewed. During feeding, the manubrium performs highly accurate flexions to points at the margin. At the same time, the oral lips flare open. The directional flexions are conducted by FMRFamide immunoreactive nerves, the lip flaring by an excitable epithelium lining the radial canals. Inhibition of swimming during feeding is due to impulses propagated centrifugally in the same epithelium. Aglantha probably evolved from an ancestor possessing a relatively simple wiring plan, as seen in other hydromedusae. Acquisition of giant axons resulted in considerable modification of this basic plan, and required novel solutions to the problems of integrating escape with non-escape circuitry.     

Muscle tone regulation during REM sleep: neural circuitry and clinical significance

Rapid eye movement (REM) sleep is a distinct behavioral state characterized by an activated cortical and hippocampal electroencephalogram (EEG) and concurrent muscle atonia. Research conducted over the past 50 years has revealed the neuronal circuits responsible for the generation and maintenance of REM sleep, as well as the pathways involved in generating the cardinal signs of REM sleep such as cortical activation and muscle atonia. The generation and maintenance of REM sleep appear to involve a widespread network in the pons and medulla. The caudal laterodorsal tegmental nucleus (cLDT) and sublaterodorsal nucleus (SLD) within the dorsolateral pons contain REM-on neurons, and the ventrolateral periaqueductal grey (vlPAG) contains REM-off neurons. The interaction between these structures is proposed to regulate REM sleep amounts. The cLDT-SLD neurons project to the basal forebrain via the parabrachial-precoeruleus (PB-PC) complex, and this pathway may be critical for the EEG activation seen during REM sleep. Descending SLD glutamatergic projections activate the ventromedial medulla, and spinal cord interneurons mediate muscle atonia and suppress phasic muscle twitches in spinal musculature. In contrast, phasic muscle twitches in the masseter muscles may be driven by glutamatergic neurons in the rostral parvicellular reticular nucleus (PCRt); however, the brain region responsible for generating phasic twitches in the other cranial muscles including facial muscles and tongue are not clear.     

Neurobiology of obsessive-compulsive disorder: insights into neural circuitry dysfunction through mouse genetics

The precise causal factors for obsessive-compulsive disorder (OCD) are not known, although, decades of research have honed in on the cortico-striatal-thalamo-cortical (CSTC) circuitry in the brain as a critical pathway involved in obsessions and the intimately linked compulsive-repetitive behaviors. Recent progress in human and mouse genetics have led to the identification of novel candidate susceptibility genes, which in turn have facilitated a more focused approach to unraveling the nature of circuitry dysfunction in OCD. The ability to perform invasive techniques in genetic animal models of OCD will be crucial for rapid advances in this field, and as such we review the most recent developments and highlight the importance of searching out common circuitry defects underlying compulsive-repetitive behaviors.     

"Thinking about not-thinking": neural correlates of conceptual processing during Zen meditation

Recent neuroimaging studies have identified a set of brain regions that are metabolically active during wakeful rest and consistently deactivate in a variety the performance of demanding tasks. This "default network" has been functionally linked to the stream of thoughts occurring automatically in the absence of goal-directed activity and which constitutes an aspect of mental behavior specifically addressed by many meditative practices. Zen meditation, in particular, is traditionally associated with a mental state of full awareness but reduced conceptual content, to be attained via a disciplined regulation of attention and bodily posture. Using fMRI and a simplified meditative condition interspersed with a lexical decision task, we investigated the neural correlates of conceptual processing during meditation in regular Zen practitioners and matched control subjects. While behavioral performance did not differ between groups, Zen practitioners displayed a reduced duration of the neural response linked to conceptual processing in regions of the default network, suggesting that meditative training may foster the ability to control the automatic cascade of semantic associations triggered by a stimulus and, by extension, to voluntarily regulate the flow of spontaneous mentation.     

Oxytocin shapes the neural circuitry of trust and trust adaptation in humans

Trust and betrayal of trust are ubiquitous in human societies. Recent behavioral evidence shows that the neuropeptide oxytocin increases trust among humans, thus offering a unique chance of gaining a deeper understanding of the neural mechanisms underlying trust and the adaptation to breach of trust. We examined the neural circuitry of trusting behavior by combining the intranasal, double-blind, administration of oxytocin with fMRI. We find that subjects in the oxytocin group show no change in their trusting behavior after they learned that their trust had been breached several times while subjects receiving placebo decrease their trust. This difference in trust adaptation is associated with a specific reduction in activation in the amygdala, the midbrain regions, and the dorsal striatum in subjects receiving oxytocin, suggesting that neural systems mediating fear processing (amygdala and midbrain regions) and behavioral adaptations to feedback information (dorsal striatum) modulate oxytocin's effect on trust. These findings may help to develop deeper insights into mental disorders such as social phobia and autism, which are characterized by persistent fear or avoidance of social interactions.     

Regulation of neural progenitor cell state by ephrin-B

Maintaining a balance between self-renewal and differentiation in neural progenitor cells during development is important to ensure that correct numbers of neural cells are generated. We report that the ephrin-B-PDZ-RGS3 signaling pathway functions to regulate this balance in the developing mammalian cerebral cortex. During cortical neurogenesis, expression of ephrin-B1 and PDZ-RGS3 is specifically seen in progenitor cells and is turned off at the onset of neuronal differentiation. Persistent expression of ephrin-B1 and PDZ-RGS3 prevents differentiation of neural progenitor cells. Blocking RGS-mediated ephrin-B1 signaling in progenitor cells through RNA interference or expression of dominant-negative mutants results in differentiation. Genetic knockout of ephrin-B1 causes early cell cycle exit and leads to a concomitant loss of neural progenitor cells. Our results indicate that ephrin-B function is critical for the maintenance of the neural progenitor cell state and that this role of ephrin-B is mediated by PDZ-RGS3, likely via interacting with the noncanonical G protein signaling pathway, which is essential in neural progenitor asymmetrical cell division.