Behavioral Neuroscience publications

Many postnatal onset neurological disorders such as autism spectrum disorders (ASDs) and intellectual disability are thought to arise largely from disruption of excitatory/inhibitory homeostasis. Although mouse models of Rett syndrome (RTT), a postnatal neurological disorder caused by loss-of-function mutations in MECP2, display impaired excitatory neurotransmission, the RTT phenotype can be largely reproduced in mice simply by removing MeCP2 from inhibitory GABAergic neurons. To determine what role excitatory signaling impairment might play in RTT pathogenesis, we generated conditional mouse models with Mecp2 either removed from or expressed solely in glutamatergic neurons. MeCP2 deficiency in glutamatergic neurons leads to early lethality, obesity, tremor, altered anxiety-like behaviors, and impaired acoustic startle response, which is distinct from the phenotype of mice lacking MeCP2 only in inhibitory neurons. These findings reveal a role for excitatory signaling impairment in specific neurobehavioral abnormalities shared by RTT and other postnatal neurological disorders.

How do you make a decision if you do not know the rules of the game? Models of sensory decision-making suggest that choices are slow if evidence is weak, but they may only apply if the subject knows the task rules. Here, we asked how the learning of a new rule influences neuronal activity in the visual (area V1) and frontal cortex (area FEF) of monkeys. We devised a new icon-selection task. On each day, the monkeys saw 2 new icons (small pictures) and learned which one was relevant. We rewarded eye movements to a saccade target connected to the relevant icon with a curve. Neurons in visual and frontal cortex coded the monkey's choice, because the representation of the selected curve was enhanced. Learning delayed the neuronal selection signals and we uncovered the cause of this delay in V1, where learning to select the relevant icon caused an early suppression of surrounding image elements. These results demonstrate that the learning of a new rule causes a transition from fast and random decisions to a more considerate strategy that takes additional time and they reveal the contribution of visual and frontal cortex to the learning process.

The harmonic structure of sounds is an important grouping cue in auditory scene analysis. The ability of ferrets to detect mistuned harmonics was measured using a go/no-go task paradigm. Psychometric functions plotting sensitivity as a function of degree of mistuning were used to evaluate behavioral performance using signal detection theory. The mean (± standard error of the mean) threshold for mistuning detection was 0.8 ± 0.1 Hz, with sensitivity indices and reaction times depending on the degree of mistuning. These data provide a basis for investigation of the neural basis for the perception of complex sounds in ferrets, an increasingly used animal model in auditory research.

Age-related hearing loss (ARHL), clinically referred to as presbycusis, is one of the three most prevalent chronic medical conditions of our elderly, with the majority of persons over the age of 60 suffering from some degree of ARHL. The progressive loss of auditory sensitivity and perceptual capability results in significant declines in workplace productivity, quality of life, cognition and abilities to communicate effectively. Aldosterone is a mineralocorticoid hormone produced in the adrenal glands and plays a role in the maintenance of key ion pumps, including the Na-K(+)-Cl co-transporter 1 or NKCC1, which is involved in homeostatic maintenance of the endocochlear potential. Previously we reported that aldosterone (1 μM) increases NKCC1 protein expression in vitro and that this up-regulation of NKCC1 was not dose-dependent (dosing range from 1 nM to 100 μM). In the current study we measured behavioral and electrophysiological hearing function in middle-aged mice following long-term systemic treatment with aldosterone. We also confirmed that blood pressure remained stable during treatment and that NKCC1 protein expression was upregulated. Pre-pulse inhibition of the acoustic startle response was used as a functional measure of hearing, and the auditory brainstem response was used as an objective measure of peripheral sensitivity. Long-term treatment with aldosterone improved both behavioral and physiological measures of hearing (ABR thresholds). These results are the first to demonstrate a protective effect of aldosterone on age-related hearing loss and pave the way for translational drug development, using aldosterone as a key component to prevent or slow down the progression of ARHL.

The anterior hypothalamic area (AHA) is an important integrative relay structure for a variety of autonomic, endocrine, and behavioral responses including feeding behavior and response to stress. However, changes in the activity of the AHA neurons during stress and feeding in freely moving rats are not clear. The present study investigated the firing rate and burst activity of neurons in the central nucleus of the AHA (cAHA) during sucrose intake in non-stressful conditions and after acute stress in freely behaving rats. Rats were implanted with micro-electrodes into the cAHA, and extracellular multi-unit activity was recorded during 1-h access to 10% sucrose in non-stressful conditions or after acute foot shock stress. Acute stress significantly reduced sucrose intake, total sucrose lick number, and lick frequency in licking clusters, and increased inter-lick intervals. At the cluster start (CS) of sucrose licking, the cAHA neurons increased (CS-excited, 20% of the recorded neurons), decreased (CS-inhibited, 42% of the neurons) or did not change (CS-nonresponsive, 38% of the neurons) their firing rate. Stress resulted in a significant increase in the firing rate of the CS-inhibited neurons by decreasing inter-spike intervals within the burst firing of these neurons. This increase in the stress-induced firing rate of the CS-inhibited neurons was accompanied by a disruption of the correlation between the firing rate of CS-inhibited and CS-nonresponsive neurons that was observed in non-stressful conditions. Stress did not affect the firing rate of the CS-excited and CS-nonresponsive neurons. However, stress changed the pattern of burst firing of the CS-excited and CS-nonresponsive neurons by decreasing and increasing the burst number in the CS-excited and CS-nonresponsive neurons, respectively. These results suggest that the cAHA neurons integrate the signals related to stress and intake of palatable food and play a role in the stress- and eating-related circuitry.

Stimulus complexity affects the response of looming sensitive neurons in a variety of animal taxa. The Lobula Giant Movement Detector/Descending Contralateral Movement Detector (LGMD/DCMD) pathway is well-characterized in the locust visual system. It responds to simple objects approaching on a direct collision course (i.e., looming) as well as complex motion defined by changes in stimulus velocity, trajectory, and transitions, all of which are affected by the presence or absence of background visual motion. In this study, we focused on DCMD responses to objects transitioning away from a collision course, which emulates a successful locust avoidance behavior. We presented each of 20 locusts with a sequence of complex three-dimensional visual stimuli in simple, scattered, and progressive flow field backgrounds while simultaneously recording DCMD activity extracellularly. DCMD responses to looming stimuli were generally characteristic irrespective of stimulus background. However, changing background complexity affected, peak firing rates, peak time, and caused changes in peak rise and fall phases. The DCMD response to complex object motion also varied with the azimuthal approach angle and the dynamics of object edge expansion. These data fit with an existing correlational model that relates expansion properties to firing rate modulation during trajectory changes.

Developmental disabilities, including attention-deficit hyperactivity disorder (ADHD), intellectual disability (ID), and autism spectrum disorders (ASD), affect one in six children in the USA. Recently, gene mutations in patched domain containing 1 (PTCHD1) have been found in ~1% of patients with ID and ASD. Individuals with PTCHD1 deletion show symptoms of ADHD, sleep disruption, hypotonia, aggression, ASD, and ID. Although PTCHD1 is probably critical for normal development, the connection between its deletion and the ensuing behavioural defects is poorly understood. Here we report that during early post-natal development, mouse Ptchd1 is selectively expressed in the thalamic reticular nucleus (TRN), a group of GABAergic neurons that regulate thalamocortical transmission, sleep rhythms, and attention. Ptchd1 deletion attenuates TRN activity through mechanisms involving small conductance calcium-dependent potassium currents (SK). TRN-restricted deletion of Ptchd1 leads to attention deficits and hyperactivity, both of which are rescued by pharmacological augmentation of SK channel activity. Global Ptchd1 deletion recapitulates learning impairment, hyper-aggression, and motor defects, all of which are insensitive to SK pharmacological targeting and not found in the TRN-restricted deletion mouse. This study maps clinically relevant behavioural phenotypes onto TRN dysfunction in a human disease model, while also identifying molecular and circuit targets for intervention.

A marked bias towards risk aversion has been observed in nearly every species tested. A minority of individuals, however, instead seem to prefer risk (repeatedly choosing uncertain large rewards over certain but smaller rewards), and even risk-averse individuals sometimes opt for riskier alternatives. It is not known how neural activity underlies such important shifts in decision-making--either as a stable trait across individuals or at the level of variability within individuals. Here we describe a model of risk-preference in rats, in which stable individual differences, trial-by-trial choices, and responses to pharmacological agents all parallel human behaviour. By combining new genetic targeting strategies with optical recording of neural activity during behaviour in this model, we identify relevant temporally specific signals from a genetically and anatomically defined population of neurons. This activity occurred within dopamine receptor type-2 (D2R)-expressing cells in the nucleus accumbens (NAc), signalled unfavourable outcomes from the recent past at a time appropriate for influencing subsequent decisions, and also predicted subsequent choices made. Having uncovered this naturally occurring neural correlate of risk selection, we then mimicked the temporally specific signal with optogenetic control during decision-making and demonstrated its causal effect in driving risk-preference. Specifically, risk-preferring rats could be instantaneously converted to risk-averse rats with precisely timed phasic stimulation of NAc D2R cells. These findings suggest that individual differences in risk-preference, as well as real-time risky decision-making, can be largely explained by the encoding in D2R-expressing NAc cells of prior unfavourable outcomes during decision-making.

The brain possesses a remarkable capacity to compensate for changes in inputs resulting from a range of sensory impairments. Developmental studies of sound localization have shown that adaptation to asymmetric hearing loss can be achieved either by reinterpreting altered spatial cues or by relying more on those cues that remain intact. Adaptation to monaural deprivation in adulthood is also possible, but appears to lack such flexibility. Here we show, however, that appropriate behavioral training enables monaurally-deprived adult humans to exploit both of these adaptive processes. Moreover, cortical recordings in ferrets reared with asymmetric hearing loss suggest that these forms of plasticity have distinct neural substrates. An ability to adapt to asymmetric hearing loss using multiple adaptive processes is therefore shared by different species and may persist throughout the lifespan. This highlights the fundamental flexibility of neural systems, and may also point toward novel therapeutic strategies for treating sensory disorders.

Listeners can perceive interleaved sequences of sounds from two or more sources as segregated streams. In humans, physical separation of sound sources is a major factor enabling such stream segregation. Here, we examine spatial stream segregation with a psychophysical measure in domestic cats. Cats depressed a pedal to initiate a target sequence of brief sound bursts in a particular rhythm and then released the pedal when the rhythm changed. The target bursts were interleaved with a competing sequence of bursts that could differ in source location but otherwise were identical to the target bursts. This task was possible only when the sources were heard as segregated streams. When the sound bursts had broad spectra, cats could detect the rhythm change when target and competing sources were separated by as little as 9.4°. Essentially equal levels of performance were observed when frequencies were restricted to a high, 4-to-25-kHz, band in which the principal spatial cues presumably were related to sound levels. When the stimulus band was restricted from 0.4 to 1.6 kHz, leaving interaural time differences as the principal spatial cue, performance was severely degraded. The frequency sensitivity of cats in this task contrasts with that of humans, who show better spatial stream segregation with low- than with high-frequency sounds. Possible explanations for the species difference includes the smaller interaural delays available to cats due to smaller sizes of their heads and the potentially greater sound-level cues available due to the cat's frontally directed pinnae and higher audible frequency range.

Objective. Micro-electrocorticography ( μ ECoG) offers a minimally invasive neural interface with high spatial resolution over large areas of cortex. However, electrode arrays with many contacts that are individually wired to external recording systems are cumbersome and make recordings in freely behaving rodents challenging. We report a novel high-density 60-electrode system for μ ECoG recording in freely moving rats. Approach. Multiplexed headstages overcome the problem of wiring complexity by combining signals from many electrodes to a smaller number of connections. We have developed a low-cost, multiplexed recording system with 60 contacts at 406 μ m spacing. We characterized the quality of the electrode signals using multiple metrics that tracked spatial variation, evoked-response detectability, and decoding value. Performance of the system was validated both in anesthetized animals and freely moving awake animals. Main results . We recorded μ ECoG signals over the primary auditory cortex, measuring responses to acoustic stimuli across all channels. Single-trial responses had high signal-to-noise ratios (SNR) (up to 25 dB under anesthesia), and were used to rapidly measure network topography within ∼10 s by constructing all single-channel receptive fields in parallel. We characterized evoked potential amplitudes and spatial correlations across the array in the anesthetized and awake animals. Recording quality in awake animals was stable for at least 30 days. Finally, we used these responses to accurately decode auditory stimuli on single trials. Significance . This study introduces (1) a μ ECoG recording system based on practical hardware design and (2) a rigorous analytical method for characterizing the signal characteristics of μ ECoG electrode arrays. This methodology can be applied to evaluate the fidelity and lifetime of any μ ECoG electrode array. Our μ ECoG-based recording system is accessible and will be useful for studies of perception and decision-making in rodents, particularly over the entire time course of behavioral training and learning.

Functional magnetic resonance imaging (fMRI) and electrocorticography (ECoG) research have been influential in revealing the functional characteristics of category-selective responses in human ventral temporal cortex (VTC). One important, but unanswered, question is how these two types of measurements might be related with respect to the VTC. Here we examined which components of the ECoG signal correspond to the fMRI response by using a rare opportunity to measure both fMRI and ECoG responses from the same individuals to images of exemplars of various categories including faces, limbs, cars and houses. Our data reveal three key findings. First, we discovered that the coupling between fMRI and ECoG responses is frequency and time dependent. The strongest and most sustained correlation is observed between fMRI and high frequency broadband (HFB) ECoG responses (30-160 hz). In contrast, the correlation between fMRI and ECoG signals in lower frequency bands is temporally transient, where the correlation is initially positive, but then tapers off or becomes negative. Second, we find that the strong and positive correlation between fMRI and ECoG signals in all frequency bands emerges rapidly around 100 ms after stimulus onset, together with the onset of the first stimulus-driven neural signals in VTC. Third, we find that the spatial topology and representational structure of category-selectivity in VTC reflected in ECoG HFB responses mirrors the topology and structure observed with fMRI. These findings of a strong and rapid coupling between fMRI and HFB responses validate fMRI measurements of functional selectivity with recordings of direct neural activity and suggest that fMRI category-selective signals in VTC are associated with feed-forward neural processing.

Bottlenose dolphins (Tursiops truncatus) use the frequency contour of whistles produced by conspecifics for individual recognition. Here we tested a bottlenose dolphin's (Tursiops truncatus) ability to recognize frequency modulated whistle-like sounds using a three alternative matching-to-sample paradigm. The dolphin was first trained to select a specific object (object A) in response to a specific sound (sound A) for a total of three object-sound associations. The sounds were then transformed by amplitude, duration, or frequency transposition while still preserving the frequency contour of each sound. For comparison purposes, 30 human participants completed an identical task with the same sounds, objects, and training procedure. The dolphin's ability to correctly match objects to sounds was robust to changes in amplitude with only a minor decrement in performance for short durations. The dolphin failed to recognize sounds that were frequency transposed by plus or minus ½ octaves. Human participants demonstrated robust recognition with all acoustic transformations. The results indicate that this dolphin's acoustic recognition of whistle-like sounds was constrained by absolute pitch. Unlike human speech, which varies considerably in average frequency, signature whistles are relatively stable in frequency, which may have selected for a whistle recognition system invariant to frequency transposition.

Tinnitus, the perception of phantom sounds, is thought to arise from increased neural synchrony, which facilitates perceptual binding and creates salient sensory features in the absence of physical stimuli. In the auditory cortex, increased spontaneous cross-unit synchrony and single-unit bursting are de facto physiological correlates of tinnitus. However, it is unknown whether neurons in the dorsal cochlear nucleus (DCN), the putative tinnitus-induction site, exhibit increased synchrony. Using a temporary-threshold shift model and gap-prepulse inhibition of the acoustic startle to assess tinnitus, we recorded spontaneous activity from fusiform cells, the principle neurons of the DCN, in normal hearing, tinnitus, and non-tinnitus guinea pigs. Synchrony and bursting, as well as spontaneous firing rate (SFR), correlated with behavioral evidence of tinnitus, and increased synchrony and bursting were associated with SFR elevation. The presence of increased synchrony and bursting in DCN fusiform cells suggests that a neural code for phantom sounds emerges in this brainstem location and likely contributes to the formation of the tinnitus percept. SIGNIFICANCE STATEMENT Tinnitus, a phantom auditory percept, is encoded by pathological changes in the neural synchrony code of perceptual processing. Increased cross-unit synchrony and bursting have been linked to tinnitus in several higher auditory stations but not in fusiform cells of the dorsal cochlear nucleus (DCN), key brainstem neurons in tinnitus generation. Here, we demonstrate increased synchrony and bursting of fusiform cell spontaneous firing, which correlate with frequency-specific behavioral measures of tinnitus. Thus, the neural representation of tinnitus emerges early in auditory processing and likely drives its pathophysiology in higher structures.

High temporal acuity of auditory processing underlies perception of speech and other rapidly varying sounds. A common measure of auditory temporal acuity in humans is the threshold for detection of brief gaps in noise. Gap-detection deficits, observed in developmental disorders, are considered evidence for “sluggish” auditory processing. Here we show, in a mouse model of gap-detection deficits, that auditory brain sensitivity to brief gaps in noise can be impaired even without a general loss of central auditory temporal acuity. Extracellular recordings in three different subdivisions of the auditory thalamus in anesthetized mice revealed a stimulus-specific, subdivision-specific deficit in thalamic sensitivity to brief gaps in noise in experimental animals relative to controls. Neural responses to brief gaps in noise were reduced, but responses to other rapidly changing stimuli unaffected, in lemniscal and nonlemniscal (but not polysensory) subdivisions of the medial geniculate body. Through experiments and modeling, we demonstrate that the observed deficits in thalamic sensitivity to brief gaps in noise arise from reduced neural population activity following noise offsets, but not onsets. These results reveal dissociable sound-onset-sensitive and sound-offset-sensitive channels underlying auditory temporal processing, and suggest that gap-detection deficits can arise from specific impairment of the sound-offset-sensitive channel. SIGNIFICANCE STATEMENT The experimental and modeling results reported here suggest a new hypothesis regarding the mechanisms of temporal processing in the auditory system. Using a mouse model of auditory temporal processing deficits, we demonstrate the existence of specific abnormalities in auditory thalamic activity following sound offsets, but not sound onsets. These results reveal dissociable sound-onset-sensitive and sound-offset-sensitive mechanisms underlying auditory processing of temporally varying sounds. Furthermore, the findings suggest that auditory temporal processing deficits, such as impairments in gap-in-noise detection, could arise from reduced brain sensitivity to sound offsets alone.

Hearing loss has been associated with cognitive decline in the elderly and is considered to be an independent risk factor for dementia. One of the most common causes for acquired sensorineural hearing loss is exposure to excessive noise, which has been found to impair learning ability and cognitive performance in human subjects and animal models. Noise exposure has also been found to depress neurogenesis in the hippocampus. However, the effect is mainly attributed to the oxidant stress of noise on the cognitive brain. In the present study, young adult CBA/CAJ mice (between 1.5 and 2 months of age) were briefly exposed a high sound level to produce moderate-to-severe hearing loss. In both the blood and hippocampus, only transient oxidative stress was observed after noise exposure. However, a deficit in spatial learning/memory was revealed 3 months after noise exposure. Moreover, the deficit was correlated with the degree of hearing loss and was associated with a decrease in neurogenesis in the hippocampus. We believe that the observed effects were likely due to hearing loss rather than the initial oxidant stress, which only lasted for a short period of time.

The cannabinoid receptor 1 (CB1R) is found at several stages in the auditory pathway, but its role in hearing is unknown. Hearing abilities were measured in CB1R knockout mice and compared to those of wild-type mice. Operant conditioning and the psychophysical Method of Constant Stimuli were used to measure audiograms, gap detection thresholds, and frequency difference limens in trained mice using the same methods and stimuli as in previous experiments. CB1R knockout mice showed deficits at frequencies above 8 kHz in their audiograms relative to wild-type mice. CB1R knockouts showed enhancements for detecting gaps in low-pass noisebursts relative to wild-type mice, but were similar for other noise conditions. Finally, the two groups of mice did not differ in their frequency discrimination abilities as measured by the frequency difference limens task. These experiments suggest that the CB1R is involved in auditory processing and lay the groundwork for future physiological experiments.

Significance Strong associations between cocaine and the environmental contexts where cocaine is administered are thought to drive relapse. The nucleus accumbens (NAc) encodes these cue–reward associations, and here we determined how cocaine alters the ability of cells in NAc to respond to drug-associated environmental stimuli to drive drug seeking. Using fiber photometry calcium imaging we define the specific population of cells, dopamine D1 receptor-expressing neurons, that encodes information about drug associations and show that these cells can be manipulated to attenuate the strength of drug associations and prevent relapse. Together, these data define a basic circuit mechanism underlying drug–context associations and suggest that pharmacotherapeutic agents aimed at D1-type neurons may help to promote sustained abstinence in cocaine abusers.

Acoustic communication signals carry information related to the types of social interactions by means of their “acoustic context,” the sequencing and temporal emission pattern of vocalizations. Here we describe responses to natural vocal sequences in adult big brown bats ( Eptesicus fuscus). We first assessed how vocal sequences modify the internal affective state of a listener (via heart rate). The heart rate of listening bats was differentially modulated by vocal sequences, showing significantly greater elevation in response to moderately aggressive sequences than appeasement or neutral sequences. Next, we characterized single-neuron responses in the basolateral amygdala (BLA) of awake, restrained bats to isolated syllables and vocal sequences. Two populations of neurons distinguished by background firing rates also differed in acoustic stimulus selectivity. Low-background neurons (<1 spike/s) were highly selective, responding on average to one tested stimulus. These may participate in a sparse code of vocal stimuli, in which each neuron responds to one or a few stimuli and the population responds to the range of vocalizations across behavioral contexts. Neurons with higher background rates (≥1 spike/s) responded broadly to tested stimuli and better represented the timing of syllables within sequences. We found that spike timing information improved the ability of these neurons to discriminate among vocal sequences and among the behavioral contexts associated with sequences compared with a rate code alone. These findings demonstrate that the BLA contains multiple robust representations of vocal stimuli that can provide the basis for emotional/physiological responses to these stimuli.

Sugar exerts its potent reinforcing effects via both gustatory and post-ingestive pathways. It is, however, unknown whether sweetness and nutritional signals engage segregated brain networks to motivate ingestion. We found in mice that separate basal ganglia circuitries mediated the hedonic and nutritional actions of sugar. During sugar intake, suppressing hedonic value inhibited dopamine release in ventral, but not dorsal, striatum, whereas suppressing nutritional value inhibited dopamine release in dorsal, but not ventral, striatum. Consistently, cell-specific ablation of dopamine-excitable cells in dorsal, but not ventral, striatum inhibited sugar's ability to drive the ingestion of unpalatable solutions. Conversely, optogenetic stimulation of dopamine-excitable cells in dorsal, but not ventral, striatum substituted for sugar in its ability to drive the ingestion of unpalatable solutions. Our data indicate that sugar recruits a distributed dopamine-excitable striatal circuitry that acts to prioritize energy-seeking over taste quality.