Neural responses to social cues in the accessory olfactory bulb are altered by context and experience.

By: Dwyer, J. F.; Weinberg, M.; Dickinson, S. Y.; Bergan, J. F.

Social interaction enhances evolutionary fitness by enabling efficient communication of physiological information between individuals. Semiochemicals, that convey socially relevant physiological information, are detected by the vomeronasal organ (VNO) which projects directly to the accessory olfactory bulb (AOB). Mitral and tufted (M/T) neurons in the AOB convey this information from the AOB to a network of brain regions particularly devoted ... more
Social interaction enhances evolutionary fitness by enabling efficient communication of physiological information between individuals. Semiochemicals, that convey socially relevant physiological information, are detected by the vomeronasal organ (VNO) which projects directly to the accessory olfactory bulb (AOB). Mitral and tufted (M/T) neurons in the AOB convey this information from the AOB to a network of brain regions particularly devoted to processing social information and affecting social behavior. The dynamics of social behaviors are shaped by both context and experience. However, our understanding of how alterations in behavior, triggered by the same social cues, correlate with moment-to-moment fluctuations in neural activity within social circuits remains limited. Here, we investigate how context and experience alter the sensory-driven activity of AOB M/T neurons using fiberphotometry and find that the context in which a stimulus is presented can be as important for determining the strength of response as the identity of the stimulus itself. less
Sensory uncertainty influences motor learning differently in blocked versus interleaved trial contexts when both feedforward and feedback processes are engaged

By: Crossley, M. J.; Hewitson, C. L.; Kaplan, D. M.

Theories of human motor learning commonly assume that the degree to which movement plans are adjusted in response to movement errors scales with the precision of sensory feedback received regarding their success. However, support for such error-scaling models has mainly come from experiments that limit the amount of correction that can occur within an ongoing movement. In contrast, we have recently shown that when this restriction is relaxed,... more
Theories of human motor learning commonly assume that the degree to which movement plans are adjusted in response to movement errors scales with the precision of sensory feedback received regarding their success. However, support for such error-scaling models has mainly come from experiments that limit the amount of correction that can occur within an ongoing movement. In contrast, we have recently shown that when this restriction is relaxed, and both within-movement and between-movement corrections co-occur, movement plans undergo large and abrupt changes that are strongly correlated with the degree of sensory uncertainty present on the previous trial and are insensitive to the magnitude and direction of the experienced movement error. Here, we show that the presence of these abrupt and error-insensitive changes can only be reliably detected when different levels of sensory precision are interleaved pseudo randomly on a trial-by-trial basis. These results augment our earlier findings and suggest that the co-occurrence of within-movement and between-movement corrections is not the only important aspect of our earlier study that challenged the error-scaling models of motor learning under uncertainty. less
Context versus aiming in motor learning when both feedforward and feedback control processes are engaged

By: Crossley, M. J.; Hewitson, C. L.; Kaplan, D. M.

Theories of human motor learning commonly assume that movement plans are adjusted in response to the precision of sensory feedback received regarding their success. However, support for this assumption has mainly come from experiments that limit feedback correction during an ongoing movement. In contrast, we have recently shown that when this restriction is relaxed, and both within-movement and between-movement corrections can occur, movement... more
Theories of human motor learning commonly assume that movement plans are adjusted in response to the precision of sensory feedback received regarding their success. However, support for this assumption has mainly come from experiments that limit feedback correction during an ongoing movement. In contrast, we have recently shown that when this restriction is relaxed, and both within-movement and between-movement corrections can occur, movement plans undergo large and abrupt changes that are strongly correlated with the degree of sensory uncertainty present on the previous trial and are insensitive to the magnitude and direction of recently experienced movement errors. A class of models in which sensory uncertainty influences an aiming process with no retention from one trial to the next best accounted for these data. Here, we examine an alternative possibility that sensory uncertainty acts as a contextual cue to shunt motor learning and control to one of many context-specific internal models. Although both aiming and context models provide good fits for our data, the aiming model performed best. less
Behavioural pharmacology predicts disrupted signalling pathways and candidate therapeutics from zebrafish mutants of Alzheimer's disease risk genes

By: Kroll, F.; Donnelly, J.; OĢˆzcan, G. G.; Mackay, E.; Rihel, J.

By exposing genes associated with disease, genomic studies provide hundreds of starting points that should lead to druggable processes. However, our ability to systematically translate these genomic findings into biological pathways remains limited. Here, we combine rapid loss-of-function mutagenesis of Alzheimer\'s risk genes and behavioural pharmacology in zebrafish to predict disrupted processes and candidate therapeutics. FramebyFrame, ou... more
By exposing genes associated with disease, genomic studies provide hundreds of starting points that should lead to druggable processes. However, our ability to systematically translate these genomic findings into biological pathways remains limited. Here, we combine rapid loss-of-function mutagenesis of Alzheimer\'s risk genes and behavioural pharmacology in zebrafish to predict disrupted processes and candidate therapeutics. FramebyFrame, our expanded package for the analysis of larval behaviours, revealed that decreased night-time sleep was common to F0 knockouts of all four late-onset Alzheimer\'s risk genes tested. We developed an online tool, ZOLTAR, which compares any behavioural fingerprint to a library of fingerprints from larvae treated with 3,674 compounds. ZOLTAR successfully predicted that sorl1 mutants have disrupted serotonin signalling and identified betamethasone as a drug which normalises the excessive day-time sleep of presenilin-2 knockout larvae with minimal side effects. Predictive behavioural pharmacology offers a general framework to rapidly link disease-associated genes to druggable pathways. less
A reappraisal of the default mode and frontoparietal networks in the common marmoset brain

By: Okuno, T.; Ichinohe, N.; Woodward, A.

In recent years the common marmoset homologue of the human default mode network (DMN) has been a hot topic of discussion in the marmoset research field. Previously, the posterior cingulate cortex regions (PGM, A19M) and posterior parietal cortex regions (LIP, MIP) were defined as the DMN, but some studies claim that these form the frontoparietal network (FPN). We restarted from a neuroanatomical point of view and identified two DMN candidates... more
In recent years the common marmoset homologue of the human default mode network (DMN) has been a hot topic of discussion in the marmoset research field. Previously, the posterior cingulate cortex regions (PGM, A19M) and posterior parietal cortex regions (LIP, MIP) were defined as the DMN, but some studies claim that these form the frontoparietal network (FPN). We restarted from a neuroanatomical point of view and identified two DMN candidates: Comp-A (which has been called both the DMN and FPN) and Comp-B. We performed GLM analysis on auditory task-fMRI and found Comp-B to be more appropriate as the DMN, and Comp-A as the FPN. Additionally, through fingerprint analysis, a DMN and FPN in the tasking human was closer to the resting common marmoset. The human DMN appears to have an advanced function that may be underdeveloped in the common marmoset brain. less
Effects of transient, persistent, and resurgent sodium currents on excitability and spike regularity in vestibular ganglion neurons

By: Baeza Loya, S.; Eatock, R. A.

Vestibular afferent neurons occur as two populations, regular and irregular, that provide distinct information about head motions. Differences in spike timing regularity are correlated with the different sensory responses important for vestibular processing. Relative to irregular afferents, regular afferents have more sustained firing patterns in response to depolarizing current steps, are more excitable, and have different complements of ion... more
Vestibular afferent neurons occur as two populations, regular and irregular, that provide distinct information about head motions. Differences in spike timing regularity are correlated with the different sensory responses important for vestibular processing. Relative to irregular afferents, regular afferents have more sustained firing patterns in response to depolarizing current steps, are more excitable, and have different complements of ion channels. Models of vestibular regularity and excitability emphasize the influence of increased expression of low-voltage-activated potassium currents in irregular neurons. We investigated the potential impact of different modes of voltage-gated sodium (NaV) current (transient, persistent, and resurgent) in cell bodies from vestibular ganglion neurons (VGNs), dissociated and cultured overnight. We hypothesized that regular VGNs would show the greatest impact of persistent (non-inactivating) NaV currents and of resurgent NaV currents, which flow when NaV channels are blocked and then unblocked. Whole-cell patch clamp experiments showed that much of the NaV current modes is carried by NaV1.6 channels. With simulations, we detected little substantial effect in any model VGN of persistent or resurgent modes on regularity of spike timing driven by postsynaptic current trains. For simulated irregular neurons, we also saw little effect on spike rate or firing pattern. For simulated regular VGNs, adding resurgent current changed the detailed timing of spikes during a current step, while the small persistent conductance (less than10% of transient NaV conductance density) strongly depolarized resting potential, altered spike waveform, and increased spike rate. These results suggest that persistent and resurgent NaV current can have a greater effect on the regular VGNs than on irregular VGNs, where low-voltage-activated K conductances dominate. less
Impact of the Excitatory-Inhibitory Neurons Ratio on Scale-Free Dynamics in a Leaky Integrate-and-Fire Model

By: Dehghani-Habibabadi, M.; Safari, N.; Shahbazi, F.; Zare, M.

The relationship between ratios of excitatory to inhibitory neurons and the brain\'s dynamic range of cortical activity is crucial. However, its full understanding within the context of cortical scale-free dynamics remains an ongoing investigation. To provide insightful observations that can improve the current understanding of this impact, and based on studies indicating that a fully excitatory neural network can induce critical behavior und... more
The relationship between ratios of excitatory to inhibitory neurons and the brain\'s dynamic range of cortical activity is crucial. However, its full understanding within the context of cortical scale-free dynamics remains an ongoing investigation. To provide insightful observations that can improve the current understanding of this impact, and based on studies indicating that a fully excitatory neural network can induce critical behavior under the influence of noise, it is essential to investigate the effects of varying inhibition within this network. Here, the impact of varying inhibitory-excitatory neuron ratios on neural avalanches and phase transition diagrams, considering a range of synaptic efficacies in a leaky integrate-and-fire model network, is examined. Our computational results show that the network exhibits critical, sub-critical, and super-critical behavior across different synaptic efficacies. In particular, a certain excitatory/inhibitory (E/I) ratio leads to a significantly extended dynamic range compared to higher or lower levels of inhibition and increases the probability of the system being in the critical regime. In this study, we used the Kuramoto order parameter and implemented a finite-size scaling analysis to determine the critical exponents associated with this transition. To characterize the criticality, we studied the distribution of neuronal avalanches at the critical point and found a scaling behavior characterized by specific exponents. less
(R,S)-ketamine's rapid-acting antidepressant effects are modulated by NR2B- containing NMDA receptors on adult-born hippocampal neurons

By: Bulthuis, N. E.; McGowan, J. C.; Ladner, L. R.; LaGamma, C. T.; Lim, S. C.; Shubeck, C. X.; Brachman, R. A.; Sydnor, E.; Pavlova, I. P.; Seo, D.-o.; Drew, M. R.; Denny, C. A.

Standard antidepressant treatments often take weeks to reach efficacy and are ineffective for many patients. (R,S)-ketamine, an N-methyl-D-aspartate (NMDA) antagonist, has been shown to be a rapid-acting antidepressant and to decrease depressive symptoms within hours of administration. While previous studies have shown the importance of the NR2B subunit of the NMDA receptor (NMDAR) on interneurons in the medial prefrontal cortex (mPFC), no st... more
Standard antidepressant treatments often take weeks to reach efficacy and are ineffective for many patients. (R,S)-ketamine, an N-methyl-D-aspartate (NMDA) antagonist, has been shown to be a rapid-acting antidepressant and to decrease depressive symptoms within hours of administration. While previous studies have shown the importance of the NR2B subunit of the NMDA receptor (NMDAR) on interneurons in the medial prefrontal cortex (mPFC), no study has investigated the influence of NR2B-expressing adult-born granule cells (abGCs). In this study, we examined whether (R,S)-ketamine\'s efficacy depends upon these adult-born hippocampal neurons using a genetic strategy to selectively ablate the NR2B subunit of the NMDAR from Nestin+ cells. To validate our findings, we also used several other transgenic lines including one in which NR2B was deleted from an interneuron (Parvalbumin (PV)+) population. We report that in male mice, NR2B expression on 6-week-old adult-born neurons is necessary for (R,S)- ketamine\'s effects on behavioral despair in the forced swim test (FST) and on hyponeophagia in the novelty suppressed feeding (NSF) paradigm, as well on fear behavior following contextual fear conditioning (CFC). In female mice, NR2B expression is necessary for effects on hyponeophagia in the NSF. We also find that ablating neurogenesis increases fear expression in CFC, which is buffered by (R,S)-ketamine administration. In line with previous studies, these results suggest that 6-week-old adult-born hippocampal neurons expressing NR2B partially modulate (R,S)-ketamine\'s rapid-acting effects. Future work targeting these 6-week-old adult- born neurons may prove beneficial for increasing the efficacy of (R,S)-ketamine\'s antidepressant actions. less
Acute loss of fingertip sensation leads to general compensatory changes in eye-hand coordination

By: Ung, K.; Yau, J.; Nordmark, P. F.

The role of sensory feedback is well established in current models of motor control, evidenced by deficits in movement coordination resulting from impaired sensory function. When vision and touch are both available for object-oriented manual behaviors, these senses can be distinctly leveraged; vision guides movement planning while touch provides feedback on hand-object interactions. How eye-hand coordination changes with the loss of somatosen... more
The role of sensory feedback is well established in current models of motor control, evidenced by deficits in movement coordination resulting from impaired sensory function. When vision and touch are both available for object-oriented manual behaviors, these senses can be distinctly leveraged; vision guides movement planning while touch provides feedback on hand-object interactions. How eye-hand coordination changes with the loss of somatosensory feedback has not been well studied. Conceivably, vision is recruited to compensate for the feedback lost when touch is abolished. We tested healthy participants on a manual dexterity task, consisting of moving small metal pegs. The task was performed before and after administration of digital anesthesia that abolished cutaneous sensations while preserving motor function with the acting hand. During peg collection, transport, and placement epochs, we tracked gaze direction and hand positions while also recording forces applied to the pegboard. We hypothesized that the nervous system selectively adapts eye-hand coordination according to the dexterity demands of the task epochs. We found that participants maintained the ability to perform the pegboard task following the loss of cutaneous feedback, albeit with longer trial times and altered force profiles. Notably, somatosensory loss was accompanied by a shift in visual behavior marked by a closer alignment between gaze and hand positions during all task epochs, even those that did not involve object manipulation. Together, these data affirm the contributions of sensory feedback to force control in service of dexterous object manipulation and reveal the non-selective nature of compensatory eye-hand coordination processes. less
Sigma receptor ligands are potent anti-prion compounds that act independently of sigma receptor binding

By: Mercer, R. C.; Le, N. T.; Houser, M. C.; Beeler, A. B.; Harris, D. A.

Prion diseases are invariably fatal neurodegenerative diseases of humans and other animals for which there are no treatment options. Previous work from our laboratory identified phenethyl piperidines as novel class of anti-prion compounds. While working to identify the molecular target(s) of these molecules, we unexpectedly discovered ten novel anti-prion compounds based on their known ability to bind to the sigma receptors, {sigma}1R and {si... more
Prion diseases are invariably fatal neurodegenerative diseases of humans and other animals for which there are no treatment options. Previous work from our laboratory identified phenethyl piperidines as novel class of anti-prion compounds. While working to identify the molecular target(s) of these molecules, we unexpectedly discovered ten novel anti-prion compounds based on their known ability to bind to the sigma receptors, {sigma}1R and {sigma}2R, which are currently being tested as therapeutic or diagnostic targets for cancer and neuropsychiatric disorders. Surprisingly, however, knockout of the respective genes encoding {sigma}1R and {sigma}2R (Sigmar1 and Tmem97), in prion infected N2a cells did not alter the anti-prion activity of these compounds, demonstrating that these receptors are not the direct targets responsible the anti-prion effects of their ligands. Further investigation of the most potent molecules established that they are efficacious against multiple prion strains and protect against downstream prion-mediated synaptotoxicity. While the precise details of the mechanism of action of these molecules remains to be determined, the present work forms the basis for further investigations of these compounds in pre-clinical studies. Given the therapeutic utility of several of the tested compounds, including rimcazole and haloperidol for neuropsychiatric conditions, (+)-pentazocine for neuropathic pain, and the ongoing clinical trials of SA 4503 and ANAVEX2-73 for ischemic stroke and Alzheimer\'s disease, respectively, this work has immediate implications for the treatment of human prion disease. less