Stable Laboratory Culture System for the Ctenophore Mnemiopsis leidyi.

Ctenophores are marine organisms attracting significant attention from evolutionary biology, molecular biology, and ecological research. Here, we describe an easy and affordable setup to maintain a stable culture of the ctenophore Mnemiopsis leidyi. The challenging delicacy of the lobate ctenophores can be met by monitoring the water quality, providing the right nutrition, and adapting the handling and tank set-up to their fragile gelatinous body plan. Following this protocol allows stable laboratory lines, a continuous supply of embryos for molecular biological studies, and independence from population responses to environmental fluctuations.

Temporal Changes in Functional and Structural Neuronal Activities in Auditory System in Non-Severe Blast-Induced Tinnitus.

Background and Objectives: Epidemiological data indicate that blast exposure is the most common morbidity responsible for mild TBI among Service Members (SMs) during recent military operations. Blast-induced tinnitus is a comorbidity frequently reported by veterans, and despite its wide prevalence, it is also one of the least understood. Tinnitus arising from blast exposure is usually associated with direct structural damage that results in a conductive and sensorineural impairment in the auditory system. Tinnitus is also believed to be initiated by abnormal neuronal activities and temporal changes in neuroplasticity. Clinically, it is observed that tinnitus is frequently accompanied by sleep disruption as well as increased anxiety. In this study, we elucidated some of the mechanistic aspects of sensorineural injury caused by exposure to both shock waves and impulsive noise. The isolated conductive auditory damage hypothesis was minimized by employing an animal model wherein both ears were protected. Materials and Methods: After the exposure, the animals' hearing circuitry status was evaluated via acoustic startle response (ASR) to distinguish between hearing loss and tinnitus. We also compared the blast-induced tinnitus against the well-established sodium salicylate-induced tinnitus model as the positive control. The state of the sensorineural auditory system was evaluated by auditory brainstem response (ABR), and this test helped examine the neuronal circuits between the cochlea and inferior colliculus. We then further evaluated the role of the excitatory and inhibitory neurotransmitter receptors and neuronal synapses in the auditory cortex (AC) injury after blast exposure. Results: We observed sustained elevated ABR thresholds in animals exposed to blast shock waves, while only transient ABR threshold shifts were observed in the impulsive noise group solely at the acute time point. These changes were in concert with the increased expression of ribbon synapses, which is suggestive of neuroinflammation and cellular energy metabolic disorder. It was also found that the onset of tinnitus was accompanied by anxiety, depression-like symptoms, and altered sleep patterns. By comparing the effects of shock wave exposure and impulsive noise exposure, we unveiled that the shock wave exerted more significant effects on tinnitus induction and sensorineural impairments when compared to impulsive noise. Conclusions: In this study, we systematically studied the auditory system structural and functional changes after blast injury, providing more significant insights into the pathophysiology of blast-induced tinnitus.

Neuroprotective Effects of a Serotonin Receptor Peptide Following Sham vs. Mild Traumatic Brain Injury in the Zucker Rat.

Aims: Accelerated cognitive decline frequently complicates traumatic brain injury. Obesity and type 2 diabetes mellitus drive peripheral inflammation which may accelerate traumatic brain injury-associated neurodegeneration. The Zucker rat harbors G-protein coupled receptor agonist IgG autoantibodies and in vitro neurotoxicity caused by these autoantibodies was prevented by a novel synthetic fragment of the serotonin 2A receptor. The aim of the present study was to test whether genetic obesity manifested in Zucker diabetic fatty rat is associated with greater spatial memory impairment before and after mild traumatic brain injury compared to Zucker lean rats. Furthermore, we investigated whether these neurodegenerative complications can be lessened by administration of a novel putative neuroprotective peptide comprised of a fragment of the second extracellular loop of the serotonin 2A receptor. Methods: Age-matched lean and fatty diabetic Zucker rats were tested in the Morris water maze (spatial memory) prior to receiving a sham-injury or lateral fluid percussion (LFP) mild traumatic brain injury. Behavioral testing was repeated at 1-week, 1-month, and 3-month intervals following injury. A synthetic peptide consisting of a portion of the 5-hydroxytryptamine (serotonin) 2A receptor (2 mg/kg) (vehicle, or an inactive scrambled version of the peptide (2 mg/kg)) was administered via intraperitoneal route every other day for 7 days after sham or LFP injury to lean rats or 7 days before and after sham or LFP injury to fatty rats. Results: Mild traumatic brain injury impaired recall of spatial memory in fatty and lean rats. Zucker fatty rats subjected to sham-injury or mild TBI experienced a significantly greater longitudinal decline in recall of spatial memory compared to lean Zucker rats. A synthetic peptide fragment of the 5-hydroxytryptamine 2A receptor significantly enhanced acquisition of spatial learning and it appeared to strengthen recall of spatial learning (one-week) after sham injury in Zucker rats. Conclusions: These data suggest that the Zucker diabetic fatty rat is a suitable animal model to investigate the role of metabolic factor(s) in accelerated cognitive decline. A novel synthetic peptide comprised of a fragment of the second extracellular loop of the human serotonin 2A receptor appeared to have neuroprotective effects on both acquisition and recall of spatial memory in subsets of Zucker rats, with relatively greater benefit in sham-injured, lean Zucker rats.

Dataset of active avoidance in Wistar-Kyoto and Sprague Dawley rats: Experimental data and reinforcement learning model code and output.

Data were collected from 40 Wistar-Kyoto (WKY) and 40 Sprague Dawley (SD) rats during an active escape-avoidance experiment. Footshock could be avoided by pressing a lever during a danger period prior to onset of shock. If avoidance did not occur, a series of footshocks was administered, and the rat could press a lever to escape (terminate shocks). For each animal, data were simplified to the presence or absence of lever press and stimuli in each 12-second time frame. Using the pre-processed dataset, a reinforcement learning (RL) model, based on an actor-critic architecture, was utilized to estimate several different model parameters that best characterized each rat's behaviour during the experiment. Once individual model parameters were determined for all 80 rats, behavioural recovery simulations were run using the RL model with each animal's "best-fit" parameters; the simulated behaviour generated avoidance data (percent of trials avoided during a given experimental session) that could be compared across simulated rats, as is customarily done with empirical data. The datasets representing both the experimental data and the model-generated data can be interpreted in various ways to gain further insight into rat behaviour during avoidance and escape learning. Furthermore, the estimated parameters for each individual rat can be compared across groups. Thus, possible between-strain differences in model parameters can be detected, which might provide insights into strain differences in learning. The software implementing the RL model can also be applied to or serve as a template for other experiments involving acquisition learning. Reference for Co-Submission: K.M. Spiegler, J. Palmieri, K.C.H. Pang, C.E. Myers, A reinforcement-learning model of active avoidance behavior: Differences between Sprague-Dawley and Wistar-Kyoto rats. Behav. Brain Res. (2020 Jun 22[epub ahead of print])  doi: 10.1016/j.bbr.2020.112784.

Serotonin 2A Receptor Autoantibodies Increase in Adult Traumatic Brain Injury In Association with Neurodegeneration.

OBJECTIVE: Traumatic brain injury (TBI) is associated with an increased risk of late neurodegenerative complications via unknown mechanisms. Circulating neurotoxic 5-hydroxytryptamine 2A receptor (5-HT2AR) autoantibodies were reported to increase in subsets of obese type 2 diabetes having microvascular complications. We tested whether 5-HT2AR autoantibodies increase in adults following traumatic brain injury in association with neurodegenerative complications. METHODS: Plasma from thirty-five middle-aged and older adult veterans (mean 65 years old) who had suffered traumatic brain injury was subjected to protein-A affinity chromatography. The resulting immunoglobulin (Ig) G fraction was tested for neurotoxicity (acute neurite retraction, and accelerated cell death) in mouse N2A neuroblastoma cells or for binding to a linear synthetic peptide corresponding to the second extracellular loop region of the human 5-HT2A receptor. RESULTS: Nearly two-thirds of traumatic brain injured-patients harbored 5-HT2AR autoantibodies in their circulation. Active TBI autoantibodies caused neurite retraction in mouse N2A neuroblastoma cells and accelerated N2A cell loss which was substantially prevented by co-incubation with a two hundred and fifty nanomolar concentration of M100907, a highly selective 5-HT2AR antagonist. Antagonists of RhoA/Rho kinase and Gq11/phospholipase C/inositol triphosphate receptor signaling pathways blocked TBI autoantibody-induced neurite retraction. Following traumatic brain injury, autoantibody binding to a 5-HT2A receptor peptide was significantly increased in patients having co-morbid Parkinson's disease (n=3), dementia (n=5), and painful neuropathy (n=8) compared to TBI subsets without neurologic or microvascular complication (n=20). Autoantibody titer was significantly elevated in TBI subsets experiencing multiple neurotraumatic exposures vs. single TBI. Plasma white blood cell, a marker of systemic inflammation, correlated significantly (correlation coefficient r =0.52; P < 0.01) with, 5-HT2A receptor peptide binding of the TBI-autoantibody. CONCLUSION: These data suggest that circulating neurotoxic 5-hydroxytryptamine 2A receptor agonist autoantibodies increase in adults following traumatic brain injury in association with late neurodegenerative complications.

A reinforcement-learning model of active avoidance behavior: Differences between Sprague Dawley and Wistar-Kyoto rats.

Avoidance behavior is a typically adaptive response performed by an organism to avert harmful situations. Individuals differ remarkably in their tendency to acquire and perform new avoidance behaviors, as seen in anxiety disorders where avoidance becomes pervasive and inappropriate. In rodent models of avoidance, the inbred Wistar-Kyoto (WKY) rat demonstrates increased learning and expression of avoidance compared to the outbred Sprague Dawley (SD) rat. However, underlying mechanisms that contribute to these differences are unclear. Computational modeling techniques can help identify factors that may not be easily decipherable from behavioral data alone. Here, we utilize a reinforcement learning (RL) model approach to better understand strain differences in avoidance behavior. An actor-critic model, with separate learning rates for action selection (in the actor) and state evaluation (in the critic), was applied to individual data of avoidance acquisition from a large cohort of WKY and SD rats. Latent parameters were extracted, such as learning rate and subjective reinforcement value of foot shock, that were then compared across groups. The RL model was able to accurately represent WKY and SD avoidance behavior, demonstrating that the model could simulate individual performance. The model determined that the perceived negative value of foot shock was significantly higher in WKY than SD rats, whereas learning rate in the actor was lower in WKY than SD rats. These findings demonstrate the utility of computational modeling in identifying underlying processes that could promote strain differences in behavioral performance.

Biological links between traumatic brain injury and Parkinson's disease.

Parkinson's Disease (PD) is a progressive neurodegenerative disorder with no cure. Clinical presentation is characterized by postural instability, resting tremors, and gait problems that result from progressive loss of A9 dopaminergic neurons in the substantia nigra pars compacta. Traumatic brain injury (TBI) has been implicated as a risk factor for several neurodegenerative diseases, but the strongest evidence is linked to development of PD. Mild TBI (mTBI), is the most common and is defined by minimal, if any, loss of consciousness and the absence of significant observable damage to the brain tissue. mTBI is responsible for a 56% higher risk of developing PD in U.S. Veterans and the risk increases with severity of injury. While the mounting evidence from human studies suggests a link between TBI and PD, fundamental questions as to whether TBI nucleates PD pathology or accelerates PD pathology in vulnerable populations remains unanswered. Several promising lines of research point to inflammation, metabolic dysregulation, and protein accumulation as potential mechanisms through which TBI can initiate or accelerate PD. Amyloid precursor protein (APP), alpha synuclein (α-syn), hyper-phosphorylated Tau, and TAR DNA-binding protein 43 (TDP-43), are some of the most frequently reported proteins upregulated following a TBI and are also closely linked to PD. Recently, upregulation of Leucine Rich Repeat Kinase 2 (LRRK2), has been found in the brain of mice following a TBI. Subset of Rab proteins were identified as biological substrates of LRRK2, a protein also extensively linked to late onset PD. Inhibition of LRRK2 was found to be neuroprotective in PD and TBI models. The goal of this review is to survey current literature concerning the mechanistic overlap between TBI and PD with a particular focus on inflammation, metabolic dysregulation, and aforementioned proteins. This review will also cover the application of rodent TBI models to further our understanding of the relationship between TBI and PD.

Distinct cellular mediators drive the Janus faces of toll-like receptor 4 regulation of network excitability which impacts working memory performance after brain injury.

The mechanisms by which the neurophysiological and inflammatory responses to brain injury contribute to memory impairments are not fully understood. Recently, we reported that the innate immune receptor, toll-like receptor 4 (TLR4) enhances AMPA receptor (AMPAR) currents and excitability in the dentate gyrus after fluid percussion brain injury (FPI) while limiting excitability in controls. Here, we examine the cellular mediators underlying TLR4 regulation of dentate excitability and its impact on memory performance. In ex vivo slices, astrocytic and microglial metabolic inhibitors selectively abolished TLR4 antagonist modulation of excitability in controls, but not in rats after FPI, demonstrating that glial signaling contributes to TLR4 regulation of excitability in controls. In glia-depleted neuronal cultures from naïve mice, TLR4 ligands bidirectionally modulated AMPAR charge transfer consistent with neuronal TLR4 regulation of excitability, as observed after brain injury. In vivo TLR4 antagonism reduced early post-injury increases in mediators of MyD88-dependent and independent TLR4 signaling without altering expression in controls. Blocking TNFα, a downstream effector of TLR4, mimicked effects of TLR4 antagonist and occluded TLR4 agonist modulation of excitability in slices from both control and FPI rats. Functionally, transiently blocking TLR4 in vivo improved impairments in working memory observed one week and one month after FPI, while the same treatment impaired memory function in uninjured controls. Together these data identify that distinct cellular signaling mechanisms converge on TNFα to mediate TLR4 modulation of network excitability in the uninjured and injured brain and demonstrate a role for TLR4 in regulation of working memory function.

Benzopyrimidodiazepinone inhibitors of TNK2.

The SAR of a series of benzopyrimidodiazepinone inhibitors of TNK2 was developed, starting from the potent and selective compound XMD8-87. A diverse set of anilines was introduced in an effort to improve the in vivo PK profile and minimize the risk of quinone diimine formation.

Convergent evolution of a vertebrate-like methylome in a marine sponge.

Vertebrates have highly methylated genomes at CpG positions, whereas invertebrates have sparsely methylated genomes. This increase in methylation content is considered a major regulatory innovation of vertebrate genomes. However, here we report that a sponge, proposed as the potential sister group to the rest of animals, has a highly methylated genome. Despite major differences in genome size and architecture, we find similarities between the independent acquisitions of the hypermethylated state. Both lineages show genome-wide CpG depletion, conserved strong transcription factor methyl-sensitivity and developmental methylation dynamics at 5-hydroxymethylcytosine enriched regions. Together, our findings trace back patterns associated with DNA methylation in vertebrates to the early steps of animal evolution. Thus, the sponge methylome challenges previous hypotheses concerning the uniqueness of vertebrate genome hypermethylation and its implications for regulatory complexity.

Reduced avoidance coping in male, but not in female rats, after mild traumatic brain injury: Implications for depression.

Although there is evidence that traumatic brain injury (mTBI) induces emotional sequelae in rats, it is unclear whether the phenotype is reminiscent of major depressive disorder (MDD) or posttraumatic stress disorder (PTSD). Three behavioral protocols with oppositional indicators for MDD or PTSD were assessed: acoustic startle responses (ASRs), eyeblink conditioning, and instrumental escape/avoidance (E/A) learning. Female and male rats were exposed to lateral fluid percussion injury (LFPi) consistent with mild TBI (mTBI) or sham (SHAM) surgery. Experiment 1 suggested that the acquisition of the classically conditioned eyeblink responses was unaffected by mTBI infemale and male rats. In Experiment 2, male and female mTBI rats acquired instrumental escape responses similar to their SHAM counterparts. Avoidance expression of female mTBI rats did not differ appreciably from female SHAM rats. However, male mTBI rats expressed avoidance at a lower rate than male SHAM rats over training. Poor coping in male rats emerged with repeated exposure to stress, suggesting that depressive behaviors in mTBI develop over time and with continued demand from stress. Severely attenuated ASRs were evident in female and male mTBI rats compared to respective SHAM rats throughout testing across the two experiments. Overall, signs among the three bidirectional assessments during the subacute period after mTBI were more indicative of MDD-like, than PTSD-like sequelae.

Anhedonia following mild traumatic brain injury in rats: A behavioral economic analysis of positive and negative reinforcement.

Psychiatric disorders affect nearly 50% of individuals who have experienced a traumatic brain injury (TBI). Anhedonia is a major symptom of numerous psychiatric disorders and is a diagnostic criterion for depression. It has recently been appreciated that reinforcement may be separated into consummatory (hedonic), motivational and decisional components, all of which may be affected differently in disease. Although anhedonia is typically assessed using positive reinforcement, the importance of stress in psychopathology suggests the study of negative reinforcement (removal or avoidance of aversive events) may be equally important. The present study investigated positive and negative reinforcement following a rat model of mild TBI (mTBI) using lateral fluid percussion. Hedonic value and motivation for reinforcement was determined by behavioral economic analyses. Following mTBI, the hedonic value of avoiding foot shock was reduced. In contrast, the hedonic value of escaping foot shock or obtaining a sucrose pellet was not altered by mTBI. Moreover, motivation to avoid or escape foot shock or to acquire sucrose was not altered by mTBI. Our results suggest that individuals experiencing mTBI find avoidance of aversive events less reinforcing, and therefore are less apt to utilize proactive control of stress.

Inhibited Personality Temperaments Translated Through Enhanced Avoidance and Associative Learning Increase Vulnerability for PTSD.

Although many individuals who experience a trauma go on to develop post-traumatic stress disorder (PTSD), the rate of PTSD following trauma is only about 15-24%. There must be some pre-existing conditions that impart increased vulnerability to some individuals and not others. Diathesis models of PTSD theorize that pre-existing vulnerabilities interact with traumatic experiences to produce psychopathology. Recent work has indicated that personality factors such as behavioral inhibition (BI), harm avoidance (HA), and distressed (Type D) personality are vulnerability factors for the development of PTSD and anxiety disorders. These personality temperaments produce enhanced acquisition or maintenance of associations, especially avoidance, which is a criterion symptom of PTSD. In this review, we highlight the evidence for a relationship between these personality types and enhanced avoidance and associative learning, which may increase risk for the development of PTSD. First, we provide the evidence confirming a relationship among BI, HA, distressed (Type D) personality, and PTSD. Second, we present recent findings that BI is associated with enhanced avoidance learning in both humans and animal models. Third, we will review evidence that BI is also associated with enhanced eyeblink conditioning in both humans and animal models. Overall, data from both humans and animals suggest that these personality traits promote enhanced avoidance and associative learning, as well as slowing of extinction in some training protocols, which all support the learning diathesis model. These findings of enhanced learning in vulnerable individuals can be used to develop objective behavioral measures to pre-identify individuals who are more at risk for development of PTSD following traumatic events, allowing for early (possibly preventative) intervention, as well as suggesting possible therapies for PTSD targeted on remediating avoidance or associative learning. Future work should explore the neural substrates of enhanced avoidance and associative learning for behaviorally inhibited individuals in both the animal model and human participants.

Insulin-like Growth Factor II: An Essential Adult Stem Cell Niche Constituent in Brain and Intestine.

Tissue-specific stem cells have unique properties and growth requirements, but a small set of juxtacrine and paracrine signals have been identified that are required across multiple niches. Whereas insulin-like growth factor II (IGF-II) is necessary for prenatal growth, its role in adult stem cell physiology is largely unknown. We show that loss of Igf2 in adult mice resulted in a ∼50% reduction in slowly dividing, label-retaining cells in the two regions of the brain that harbor neural stem cells. Concordantly, induced Igf2 deletion increased newly generated neurons in the olfactory bulb accompanied by hyposmia, and caused impairments in learning and memory and increased anxiety. Induced Igf2 deletion also resulted in rapid loss of stem and progenitor cells in the crypts of Lieberkühn, leading to body-weight loss and lethality and the inability to produce organoids in vitro. These data demonstrate that IGF-II is critical for multiple adult stem cell niches.

Experimental traumatic brain injury results in estrous cycle disruption, neurobehavioral deficits, and impaired GSK3ß/ß-catenin signaling in female rats.

An estimated 2.8 million traumatic brain injuries (TBI) occur within the United States each year. Approximately 40% of new TBI cases are female, however few studies have investigated the effects of TBI on female subjects. In addition to typical neurobehavioral sequelae observed after TBI, such as poor cognition, impaired behavior, and somatic symptoms, women with TBI report amenorrhea or irregular menstrual cycles suggestive of disruptions in the hypothalamic-pituitary-gonadal (HPG) axis. HPG dysfunction following TBI has been linked to poor functional outcome in men and women, but the mechanisms by which this may occur or relate to behavior has not been fully developed or ascertained. The present study determined if TBI resulted in HPG axis perturbations in young adult female Sprague Dawley rats, and whether TBI was associated with cognitive and sensorimotor deficits. Following lateral fluid percussion injury, injured females spent significantly more time in diestrus compared to sham females, consistent with a persistent low sex-steroid hormone state. Injured females displayed significantly reduced 17ß-estradiol (E2) and luteinizing hormone levels. Concomitantly, injured females were impaired in spatial working memory compared to shams. Impaired GSK3ß/ß-catenin signaling related to synaptic changes was evident one-week post-injury in the hippocampus among injured females compared to sham females, and this impairment paralleled the deficits in spatial working memory. Sensorimotor function, as evidenced by suppression of the acoustic startle response, was chronically impaired even after normal estrous cycling resumed. These data demonstrate that TBI results in estrous cycle impairments, memory dysfunction, and perturbations in GSK3ß/ß-catenin signaling, suggesting a potential mechanism for HPG-mediated cognitive impairment following TBI.

Danger and safety signals independently influence persistent pathological avoidance in anxiety-vulnerable Wistar Kyoto rats: A role for impaired configural learning in anxiety vulnerability.

Pathological avoidance behavior in anxiety and anxiety-related disorders has a large role in the persistence and severity of disease. Individuals are cued to avoid potential aversive events by learned danger and safety signals in the environment. Individuals with anxiety demonstrate a bias to utilize danger signals more than safety signals, in contrast to those without these disorders. Therefore, the present study investigated if danger and safety signals differentially influenced persistent avoidance in an animal model of anxiety-vulnerability, the Wistar Kyoto (WKY) rat, relative to the outbred Sprague Dawley (SD) rat. Persistent avoidance was assessed using extinction protocols. When danger or safety signals were present during extinction, WKY rats were slower to extinguish the avoidance response compared to SD rats. In contrast, when danger and safety signals were both present during extinction, WKY and SD rats extinguished at a similar rate. Differences in contextual and configural learning were explored as potential causes of the strain differences in the use of safety and danger signals in avoidance extinction. Strains did not differ in avoidance extinction when context was manipulated. However, WKY rats were impaired in configural learning using a negative patterning task. The results indicate that danger and safety signals may impair avoidance extinction in anxiety-vulnerable individuals due to impaired configural learning. These findings have important implications for understanding the etiology of anxiety disorders and may improve their diagnosis and treatment.

Early metazoan cell type diversity and the evolution of multicellular gene regulation.

A hallmark of metazoan evolution is the emergence of genomic mechanisms that implement cell-type-specific functions. However, the evolution of metazoan cell types and their underlying gene regulatory programmes remains largely uncharacterized. Here, we use whole-organism single-cell RNA sequencing to map cell-type-specific transcription in Porifera (sponges), Ctenophora (comb jellies) and Placozoa species. We describe the repertoires of cell types in these non-bilaterian animals, uncovering diverse instances of previously unknown molecular signatures, such as multiple types of peptidergic cells in Placozoa. Analysis of the regulatory programmes of these cell types reveals variable levels of complexity. In placozoans and poriferans, sequence motifs in the promoters are predictive of cell-type-specific programmes. By contrast, the generation of a higher diversity of cell types in ctenophores is associated with lower specificity of promoter sequences and the existence of distal regulatory elements. Our findings demonstrate that metazoan cell types can be defined by networks of transcription factors and proximal promoters, and indicate that further genome regulatory complexity may be required for more diverse cell type repertoires.

Ketamine facilitates extinction of avoidance behavior and enhances synaptic plasticity in a rat model of anxiety vulnerability: Implications for the pathophysiology and treatment of anxiety disorders.

Anxiety disorders and posttraumatic stress disorder (PTSD) share a common feature of pathological avoidance behavior. The Wistar Kyoto (WKY) rat has been used as a model of anxiety vulnerability, expressing a behaviorally inhibited temperament, acquiring avoidance behavior more rapidly and displaying extinction-resistant avoidance compared to Sprague Dawley (SD) rats. Subanesthetic levels of ketamine have gained attention as a rapid antidepressant in treatment-resistant depression. While traditional antidepressants are commonly used to treat anxiety disorders and PTSD, the therapeutic utility of ketamine for these disorders is much less understood. The hippocampus is critical for the actions of antidepressants, is a structure implicated in anxiety disorders and PTSD, and is necessary for extinction of avoidance in SD rats. WKY rats have impaired hippocampal long-term potentiation (LTP), suggesting that persistent avoidance in WKY rats may be due to deficient hippocampal synaptic plasticity. In the present study, we hypothesized that ketamine would facilitate extinction of avoidance learning in WKY rats, and do so by enhancing hippocampal synaptic plasticity. As predicted, ketamine facilitated extinction of avoidance behavior in a subset of WKY rats (responders), with effects lasting at least three weeks. Additionally, LTP in these rats was enhanced by ketamine. Ketamine was not effective in facilitating avoidance extinction or in modifying LTP in WKY non-responders. The results suggest that subanesthetic levels of ketamine may be useful for treating anxiety disorders by reducing avoidance behaviors when combined with extinction conditions. Moreover, ketamine may have its long-lasting behavioral effects through enhancing hippocampal synaptic plasticity.

Differential use of danger and safety signals in an animal model of anxiety vulnerability: The behavioral economics of avoidance.

Differential processing of danger and safety signals may underlie symptoms of anxiety disorders and posttraumatic stress disorder. One symptom common to these disorders is pathological avoidance. The present study examined whether danger and safety signals influence avoidance differently in anxiety-vulnerable Wistar-Kyoto (WKY) rats and Sprague Dawley (SD) rats. SD and WKY rats were tested in a novel progressive ratio avoidance task with and without danger or safety signals. Two components of reinforcement, hedonic value and motivation, were determined by fitting an exponentiated demand equation to the data. Hedonic value of avoidance did not differ between SD and WKY rats, but WKY rats had greater motivation to avoid than SD rats. Removal of the safety signal reduced motivation to avoid in SD, but not WKY, rats. Removal of the danger signal did not alter avoidance in either strain. When danger and safety signals were presented simultaneously, WKY rats responded to the danger signals, whereas SD rats responded to the safety signal. The results provide evidence that 1) safety signals enhance motivation to avoid in SD rats, 2) both danger and safety signals influence motivation in WKY rats, and 3) danger signals take precedence over safety signals when presented simultaneously in WKY rats. Thus, anxiety vulnerability is associated with preferential use of danger signals to motivate avoidance. The differential use of danger and safety signals has important implications for the etiology and treatment of pathological avoidance in anxiety disorders and posttraumatic stress disorder.

Convergent evolution of bilaterian nerve cords.

It has been hypothesized that a condensed nervous system with a medial ventral nerve cord is an ancestral character of Bilateria. The presence of similar dorsoventral molecular patterns along the nerve cords of vertebrates, flies, and an annelid has been interpreted as support for this scenario. Whether these similarities are generally found across the diversity of bilaterian neuroanatomies is unclear, and thus the evolutionary history of the nervous system is still contentious. Here we study representatives of Xenacoelomorpha, Rotifera, Nemertea, Brachiopoda, and Annelida to assess the conservation of the dorsoventral nerve cord patterning. None of the studied species show a conserved dorsoventral molecular regionalization of their nerve cords, not even the annelid Owenia fusiformis, whose trunk neuroanatomy parallels that of vertebrates and flies. Our findings restrict the use of molecular patterns to explain nervous system evolution, and suggest that the similarities in dorsoventral patterning and trunk neuroanatomies evolved independently in Bilateria.