The impairment of cold-evoked activation of brown adipose tissue (BAT) in rats fed a high-fat diet (HFD) requires the activity of a vagal afferent to the medial nucleus of the solitary tract (mNTS). We determined the role of transient receptor potential vanilloid 1 (TRPV1) activation in the mNTS, and of a dynorphin input to the median preoptic nucleus (MnPO) in the impaired BAT thermogenic response to cold in HFD-fed rats. The levels of some linoleic acid (LA) metabolites, which can act as endogenous TRPV1 agonists, were elevated in the NTS of HFD rats compared with chow-fed rats. In HFD rats, nanoinjections of the TRPV1 antagonist, capsazepine (CPZ) in the NTS rescued the impaired BAT sympathetic nerve activity (BAT SNA) and thermogenic responses to cold. In contrast, in chow-fed rats, cold-evoked BAT SNA and BAT thermogenesis were not changed by nanoinjections of CPZ into the NTS. Axon terminals of NTS neurons that project to the dorsal lateral parabrachial nucleus (LPBd) were closely apposed to LPBd neu...

With the advent of tools for recording and manipulating activity with high spatiotemporal resolution in defined neural circuits in behaving animals, behavioral neuroscience is now tasked with establishing field-wide standards for implementing and interpreting these powerful approaches. Theoretical frameworks for what constitute proof of fundamental neurobiological principles is an ongoing and frequently debated topic. On the other hand, standardizing interpretation of individual experimental findings to avoid spurious conclusions in practice has received less attention. Even within subfields, similar assays are often used to support widely disparate conclusions which in part has contributed to a slew of studies claiming highly specified functions for cell types and circuits which are often in direct disagreement with one another. In this opinion piece, we discuss common pitfalls in design and interpretation of approaches for recording or manipulating neural activity in animal models of motivated behavior. ...

Secondary damage after spinal cord injury (SCI) occurs because of a sequence of events after the initial injury, including exacerbated inflammation that contributes to increased lesion size and poor locomotor recovery. Thus, mitigating secondary damage is critical to preserve neural tissue and improve neurologic outcome. In this work, we examined the therapeutic potential of a novel antisense oligonucleotide (ASO) with special chemical modifications [2′-deoxy-2-fluoro-D-arabinonucleic acid (FANA) ASO] for specifically inhibiting an inflammatory molecule in the injured spinal cord. The chemokine CCL3 plays a complex role in the activation and attraction of immune cells and is upregulated in the injured tissue after SCI. We used specific FANA ASO to inhibit CCL3 in a contusive mouse model of murine SCI. Our results show that self-delivering FANA ASO molecules targeting the chemokine CCL3 penetrate the spinal cord lesion site and suppress the expression of CCL3 transcripts. Furthermore, they reduce other proi...

Experimental models of epilepsy are useful to identify potential mechanisms of epileptogenesis, seizure genesis, comorbidities, and treatment efficacy. The kainic acid (KA) model is one of the most commonly used. Several modes of administration of KA exist, each producing different effects in a strain-, species-, gender-, and age-dependent manner. In this review, we discuss the advantages and limitations of the various forms of KA administration (systemic, intrahippocampal, and intranasal), as well as the histologic, electrophysiological, and behavioral outcomes in different strains and species. We attempt a personal perspective and discuss areas where work is needed. The diversity of KA models and their outcomes offers researchers a rich palette of phenotypes, which may be relevant to specific traits found in patients with temporal lobe epilepsy.

Mutations in the presenilin genes ( PS1 , PS2 ) have been linked to the majority of familial Alzheimer’s disease (AD). Although great efforts have been made to investigate pathogenic PS mutations, which ultimately cause an increase in the toxic form of β-amyloid (Aβ), the intrinsic physiological functions of PS in human neurons remain to be determined. In this study, to investigate the physiological roles of PS in human neurons, we generated PS1 conditional knock-out (KO) induced pluripotent stem cells (iPSCs), in which PS1 can be selectively abrogated under Cre transduction with or without additional PS2 KO. We showed that iPSC-derived neural progenitor cells (NPCs) do not confer a maintenance ability in the absence of both PS1 and PS2, showing the essential role of PS in Notch signaling. We then generated PS -null human cortical neurons, where PS1 was intact until full neuronal differentiation occurred. Aβ40 production was reduced exclusively in human PS1 / PS2 -null neurons along with a concomitant accu...

Background noise strongly penalizes auditory perception of speech in humans or vocalizations in animals. Despite this, auditory neurons are still able to detect communications sounds against considerable levels of background noise. We collected neuronal recordings in cochlear nucleus (CN), inferior colliculus (IC), auditory thalamus, and primary and secondary auditory cortex in response to vocalizations presented either against a stationary or a chorus noise in anesthetized guinea pigs at three signal-to-noise ratios (SNRs; −10, 0, and 10 dB). We provide evidence that, at each level of the auditory system, five behaviors in noise exist within a continuum, from neurons with high-fidelity representations of the signal, mostly found in IC and thalamus, to neurons with high-fidelity representations of the noise, mostly found in CN for the stationary noise and in similar proportions in each structure for the chorus noise. The two cortical areas displayed fewer robust responses than the IC and thalamus. Furtherm...

The motor thalamus relays signals from subcortical structures to the motor cortical areas. Previous studies in songbirds and rodents suggest that cortical feedback inputs crucially contribute to the generation of movement-related activity in the motor thalamus. In primates, however, it remains uncertain whether the corticothalamic projections may play a role in shaping neuronal activity in the motor thalamus. Here, using an optogenetic inactivation technique with the viral vector system expressing halorhodopsin, we investigated the role of cortical input in modulating thalamic neuronal activity during goal-directed behavior. In particular, we assessed whether the suppression of signals originating from the supplementary eye field at the corticothalamic terminals could change the task-related neuronal modulation in the oculomotor thalamus in monkeys performing a self-initiated saccade task. We found that many thalamic neurons exhibited changes in their firing rates depending on saccade direction or task eve...

Past social experience affects the circuitry responsible for producing and interpreting current behaviors. The social behavior network (SBN) is a candidate neural ensemble to investigate the consequences of early-life social isolation. The SBN interprets and produces social behaviors, such as vocalizations, through coordinated patterns of activity (functional connectivity) between its multiple nuclei. However, the SBN is relatively unexplored with respect to murine vocal processing. The serotonergic system is sensitive to past experience and innervates many nodes of the SBN; therefore, we tested whether serotonin signaling interacts with social experience to affect patterns of immediate early gene (IEG; cFos) induction in the male SBN following playback of social vocalizations. Male mice were separated into either social housing of three mice per cage or into isolated housing at 18–24 d postnatal. After 28–30 d in housing treatment, mice were parsed into one of three drug treatment groups: control, fenflur...

The human auditory system is exceptional at comprehending an individual speaker even in complex acoustic environments. Because the inner ear, or cochlea, possesses an active mechanism that can be controlled by subsequent neural processing centers through descending nerve fibers, it may already contribute to speech processing. The cochlear activity can be assessed by recording otoacoustic emissions (OAEs), but employing these emissions to assess speech processing in the cochlea is obstructed by the complexity of natural speech. Here, we develop a novel methodology to measure OAEs that are related to the time-varying harmonic structure of speech [speech-distortion-product OAEs (DPOAEs)]. We then employ the method to investigate the effect of selective attention on the speech-DPOAEs. We provide tentative evidence that the speech-DPOAEs are larger when the corresponding speech signal is attended than when it is ignored. Our development of speech-DPOAEs opens up a path to further investigations of the contribut...

For some individuals, social stress is a risk factor for psychiatric disorders characterized by adolescent onset, prefrontal cortex (PFC) dysfunction and cognitive impairments. Social stress may be particularly harmful during adolescence when dopamine (DA) axons are still growing to the PFC, rendering them sensitive to environmental influences. The guidance cue Netrin-1 and its receptor, DCC, coordinate to control mesocorticolimbic DA axon targeting and growth during this age. Here, we adapted the accelerated social defeat (AcSD) paradigm to expose male mice to social stress in either adolescence or adulthood and categorized them as “resilient” or “susceptible” based on social avoidance behavior. We examined whether stress would alter the expression of DCC and Netrin-1 in mesolimbic DA regions and would have enduring consequences on PFC DA connectivity and cognition. While in adolescence the majority of mice are resilient but exhibit risk-taking behavior, AcSD in adulthood leads to a majority of susceptibl...