The laboratory mouse is an emerging model for context-dependent vocal signaling and reception. Mouse ultrasonic vocalizations are robustly produced in social contexts. In adults, male vocalization during courtship has become a model of interest for signal-receiver interactions. These vocalizations can be grouped into syllable types that are consistently produced by different subspecies and strains of mice. Vocalizations are unique to individuals, vary across development, and depend on social housing conditions. The behavioral significance of different syllable types, including the contexts in which different vocalizations are made and the responses listeners have to different types of vocalizations, is not well understood. We examined the effect of female presence and estrous state on male vocalizations by exploring the use of syllable types and the parameters of syllables during courtship. We also explored correlations between vocalizations and other behaviors. These experimental manipulations produced four main findings: 1) vocalizations varied among males, 2) the production of USVs and an increase in the use of a specific syllable type were temporally related to mounting behavior, 3) the frequency (kHz), bandwidth, and duration of syllables produced by males were influenced by the estrous phase of female partners, and 4) syllable types changed when females were removed. These findings show that mouse ultrasonic courtship vocalizations are sensitive to changes in female phase and presence, further demonstrating the context-sensitivity of these calls.

Acute activation of innate immune response in the brain, or neuroinflammation, protects this vital organ from a range of external pathogens and promotes healing after traumatic brain injury. However, chronic neuroinflammation leading to the activation of immune cells like microglia and astrocytes causes damage to the nervous tissue, and it is causally linked to a range of neurodegenerative diseases such as Alzheimer's diseases (AD), Multiple Sclerosis (MS), Parkinson's disease (PD), and many others. While neuroinflammation is a key target for a range of neuropathological diseases, there is a lack of effective countermeasures to tackle it, and existing experimental therapies require fairly invasive intracerebral and intrathecal delivery due to difficulty associated with the therapeutic crossover between the blood-brain barrier, making such treatments impractical to treat neuroinflammation long-term. Here, we present the development of an optimal neurotherapeutic using our Nanoligomer Discovery Engine, by screening downregulation of several proinflammatory cytokines (e.g., Interleukin-1β or IL-1β, tumor necrosis factor-alpha or TNFα, TNF receptor 1 or TNFR1, Interleukin 6 or IL-6), inflammasomes (e.g., NLRP1), key transcription factors (e.g., nuclear factor kappa-B or NF-κβ) and their combinations, as upstream regulators and canonical pathway targets, to identify and validate the best-in-class treatment. Using our high-throughput drug discovery, target validation, and lead molecule identification via a bioinformatics and artificial intelligence-based ranking method to design sequence-specific peptide molecules to up-or downregulate gene expression of the targeted gene at will, we used our discovery engine to perturb and identify most effective upstream regulators and canonical pathways for therapeutic intervention to reverse neuroinflammation. The lead neurotherapeutic was a combination of Nanoligomers targeted to NF-κβ (SB.201.17D.8_NF-κβ1) and TNFR1 (SB.201.18D.6_TNFR1), which were identified using in vitro cell-based screening in donor-derived human astrocytes and further validated in vivo using a mouse model of lipopolysaccharide (LPS)-induced neuroinflammation. The combination treatment SB_NI_111 was delivered without any special formulation using a simple intraperitoneal injection of low dose (5 mg/kg) and was found to significantly suppress the expression of LPS-induced neuroinflammation in mouse hippocampus. These results point to the broader applicability of this approach towards the development of therapies for chronic neuroinflammation-linked neurodegenerative diseases, sleep countermeasures, and others, and the potential for further investigation of the lead neurotherapeutic molecule as reversible gene therapy.

In the face of changing behavioral situations, plasticity of sensory systems can be a valuable mechanism to facilitate appropriate behavioral responses. In the auditory system, the neurotransmitter serotonin is an important messenger for context-dependent regulation because it is sensitive to both external events and internal state, and it modulates neural activity. In male mice, serotonin increases in the auditory midbrain region, the inferior colliculus (IC), in response to changes in behavioral context such as restriction stress and social contact. Female mice have not been measured in similar contexts, although the serotonergic system is sexually dimorphic in many ways. In the present study, we investigated the effects of sex, experience and estrous state on the fluctuation of serotonin in the IC across contexts, as well as potential relationships between behavior and serotonin. Contrary to our expectation, there were no sex differences in increases of serotonin in response to a restriction stimulus. Both sexes had larger increases in second exposures, suggesting experience plays a role in serotonergic release in the IC. In females, serotonin increased during both restriction and interactions with males; however, the increase was more rapid during restriction. There was no effect of female estrous phase on the serotonergic change for either context, but serotonin was related to behavioral activity in females interacting with males. These results show that changes in behavioral context induce increases in serotonin in the IC by a mechanism that appears to be uninfluenced by sex or estrous state, but may depend on experience and behavioral activity.

No abstract

Rates of posttraumatic stress disorder (PTSD) are three times higher in traumatically injured populations than the general population, yet limited brief, valid measures for assessing PTSD symptom severity exist. The PTSD Checklist for DSM‐5 (PCL‐5) is a valid, efficient measure of symptom severity, but its completion is time consuming. Subsequently, abbreviated four‐ and eight‐item versions were developed using the Mini‐International Neuropsychiatric Interview–7 PTSD module and validated in Veteran samples. This study aimed to validate these abbreviated versions using the Clinician‐Administered PTSD Scale for DSM‐5 (CAPS‐5), the gold standard for PTSD diagnosis, in a traumatically injured civilian population. Participants were 251 traumatically injured adults (Mage = 42.52 years; 69.3% male; 50.2% Caucasian) recruited from a Level 1 trauma center inpatient unit; 32.3% and 17.9% of participants experienced a motor vehicle crash or gunshot wound, respectively. The CAPS‐5 and PCL‐5 were administered approximately 6.5 months postinjury. We examined whether compared to the full PCL‐5, the abbreviated versions would adequately differentiate between participants with and without a CAPS‐5 PTSD diagnosis. The abbreviated versions were highly correlated with the total scale and showed good‐to‐excellent internal consistency. The diagnostic utility of the abbreviated measures was comparable to that of the total scale regarding sensitivity, suggesting they may be useful as abbreviated screening tools; however, the total scale functioned better regarding specificity. The abbreviated versions of the PCL‐5 may be useful screening instruments in the long‐term care of traumatic injury survivors and may be more likely to be implemented across routine clinical and research contexts.

Interval-counting neurons (ICNs) respond after a threshold number of sound pulses have occurred with specific intervals; a single aberrant interval can reset the counting process. Female gray treefrogs, Hyla chrysoscelis and H. versicolor, discriminate against synthetic 'calls' possessing a single interpulse interval 2-3 three times the optimal value, suggesting that ICNs are important for call recognition. The calls of H. versicolor consist of pulses that are longer in duration, rise more slowly in amplitude and are repeated at a slower rate than those of H. chrysoscelis. Results of recordings from midbrain auditory neurons in these species include: (1) ICNs were found in both species and their temporal selectivity appeared to result from interplay between excitation and inhibition; (2) band-pass cells in H. versicolor were tuned to slower pulse rates than those in H. chrysoscelis; (3) ICNs that were selective for slow-rise pulse shape were found almost exclusively in H. versicolor, but fast-rise-selective neurons were found in both species, and (4) band-suppression ICNs in H. versicolor showed response minima at higher pulse rates than those in H. chrysoscelis. Selectivity of midbrain ICNs for pulse rise time and repetition rate thus correlate well with discriminatory abilities of these species that promote reproductive isolation.

Sound duration is important in acoustic communication, including speech recognition in humans. Although duration-selective auditory neurons have been found, the underlying mechanisms are unclear.To investigate these mechanisms we combined in vivo whole-cell patch recordings from midbrain neurons, extraction of excitatory and inhibitory conductances, and focal pharmacological manipulations. We show that selectivity for short-duration stimuli results from integration of short-latency, sustained inhibition with delayed, phasic excitation; active membrane properties appeared to amplify responses to effective stimuli. Blocking GABA A receptors attenuated stimulus-related inhibition, revealed suprathreshold excitation at all stimulus durations, and decreased short-pass selectivity without changing resting potentials. Blocking AMPA and NMDA receptors to attenuate excitation confirmed that inhibition tracks stimulus duration and revealed no evidence of postinhibitory rebound depolarization inherent to coincidence models of duration selectivity. These results strongly support an anticoincidence mechanism of short-pass selectivity, wherein inhibition and suprathreshold excitation show greatest temporal overlap for long duration stimuli.whole-cell | GABA | synaptic conductance | gabazine | inferior colliculus A principal goal in neuroscience is to understand the computational mechanisms that underlie selectivity for particular types of information. Sensory neurons have been identified that show selectivity for biologically relevant stimulus features; however, the underlying mechanisms are, in most cases, poorly understood. A notable exception involves mechanisms of selectivity for sound duration, particularly in bat and anuran auditory systems (1-3). Duration-selective neurons were first found in the midbrain torus semicircularis of anurans (4, 5), homolog of the mammalian inferior colliculus (IC) and referred to here as the IC an . In anurans and many mammalian species, midbrain neurons have been identified that show short-pass, band-pass, or long-pass duration selectivity (3, 6-11). These neurons code for temporal properties of acoustic signals that are important in communication and echolocation. Processing sound duration is also critical for human speech communication, and deficiencies in the neural processing of this and other temporal information feature prominently in disorders of speech recognition (12, 13). Hence, understanding the mechanisms of duration selectivity is of considerable importance.Several models of duration selectivity have been proposed. The first model, derived from extracellular recordings in the anuran IC (4), incorporates delayed, onset excitation and shortlatency offset excitation that coincide for the optimal stimulus duration (Fig. 1A). Subsequent extracellular recordings from IC neurons in bats showed that blocking receptors of inhibitory neurotransmitters eliminated, or greatly attenuated, duration selectivity (14-16). Further, the temporal pattern of discharges shifted from offset to onse...

BackgroundPsychopathy is a personality disorder characterized by interpersonal and emotional abnormalities (e.g., lack of empathy and guilt) and antisocial behavior. Psychopathy has been associated with a number of structural brain abnormalities, most notably in orbital frontal and anterior/medial temporal regions, that may underlie psychopathic individuals' problematic behaviors. Past research evaluating cortical structure in psychopathy has considered thickness and volume, but to date no study has investigated differences in cortical gyrification, a measure of cortical complexity thought to reflect early neurodevelopmental cortical connectivity.MethodsWe measured the local gyrification index (LGI) in a sample of 716 adult male inmates and performed a whole brain analysis assessing the relationship between LGI and total and factor scores on the Hare Psychopathy Checklist-Revised (PCL-R).ResultsPCL-R scores were negatively associated with LGI measures within the right hemisphere in the midcingulate cortex (MCC) and adjacent regions of the superior frontal gyrus as well as lateral superior parietal cortex. Additionally, PCL-R Factor 1 scores (interpersonal/affective traits) predicted less LGI within the right MCC and adjacent dorsomedial frontal cortex and greater LGI in bilateral occipital cortex. Scores on PCL-R Factor 2, indicating impulsivity and antisocial behaviors, did not predict LGI in any regions.ConclusionsThese findings suggest that psychopathy, particularly the interpersonal and affective traits, are associated with specific structural abnormalities that form during neurodevelopment and these abnormalities may underlie aberrant brain functioning in regions important in emotional processing and cognitive control.