Behavioral Neuroscience publications

The ventral striatum is critical for evaluating reward information and the initiation of goal-directed behaviors. The many cellular, afferent, and efferent similarities between the ventral striatum's nucleus accumbens and olfactory tubercle (OT) suggests the distributed involvement of neurons within the ventral striatopallidal complex in motivated behaviors. Although the nucleus accumbens has an established role in representing goal-directed actions and their outcomes, it is not known whether this function is localized within the nucleus accumbens or distributed also within the OT. Answering such a fundamental question will expand our understanding of the neural mechanisms underlying motivated behaviors. Here we address whether the OT encodes natural reinforcers and serves as a substrate for motivational information processing. In recordings from mice engaged in a novel water-motivated instrumental task, we report that OT neurons modulate their firing rate during initiation and progression of the instrumental licking behavior, with some activity being internally generated and preceding the first lick. We further found that as motivational drive decreases throughout a session, the activity of OT neurons is enhanced earlier relative to the behavioral action. Additionally, OT neurons discriminate the types and magnitudes of fluid reinforcers. Together, these data suggest that the processing of reward information and the orchestration of goal-directed behaviors is a global principle of the ventral striatum and have important implications for understanding the neural systems subserving addiction and mood disorders. SIGNIFICANCE STATEMENT Goal-directed behaviors are widespread among animals and underlie complex behaviors ranging from food intake, social behavior, and even pathological conditions, such as gambling and drug addiction. The ventral striatum is a neural system critical for evaluating reward information and the initiation of goal-directed behaviors. Here we show that neurons in the olfactory tubercle subregion of the ventral striatum robustly encode the onset and progression of motivated behaviors, and discriminate the type and magnitude of a reward. Our findings are novel in showing that olfactory tubercle neurons participate in such coding schemes and are in accordance with the principle that ventral striatum substructures may cooperate to guide motivated behaviors.

Low-level lead exposure is a risk factor for cognitive and learning disabilities in children and has been specifically associated with deficits in auditory temporal processing that impair aural language and reading abilities. Here, we show that rats exposed to low levels of lead in early life display a significant behavioral impairment in an auditory temporal rate discrimination task. Lead exposure also results in a degradation of the neuronal repetition-rate following capacity and response synchronization in primary auditory cortex. A modified go/no-go repetition-rate discrimination task applied in adult animals for ∼50 days nearly restores to normal these lead-induced deficits in cortical temporal fidelity. Cortical expressions of parvalbumin, brain-derived neurotrophic factor, and NMDA receptor subunits NR2a and NR2b, which are down-regulated in lead-exposed animals, are also partially reversed with training. These studies in an animal model identify the primary auditory cortex as a novel target for low-level lead exposure and demonstrate that perceptual training can ameliorate lead-induced deficits in cortical discrimination between sound sequences.

Hearing-impaired individuals experience difficulties in detecting or understanding speech, especially in background sounds within the same frequency range. However, normally hearing (NH) human listeners experience less difficulty detecting a target tone in background noise when the envelope of that noise is temporally gated (modulated) than when that envelope is flat across time (unmodulated). This perceptual benefit is called modulation masking release (MMR). When flanking masker energy is added well outside the frequency band of the target, and comodulated with the original modulated masker, detection thresholds improve further (MMR+). In contrast, if the flanking masker is antimodulated with the original masker, thresholds worsen (MMR−). These interactions across disparate frequency ranges are thought to require central nervous system (CNS) processing. Therefore, we explored the effect of developmental conductive hearing loss (CHL) in gerbils on MMR characteristics, as a test for putative CNS mechanisms. The detection thresholds of NH gerbils were lower in modulated noise, when compared with unmodulated noise. The addition of a comodulated flanker further improved performance, whereas an antimodulated flanker worsened performance. However, for CHL-reared gerbils, all three forms of masking release were reduced when compared with NH animals. These results suggest that developmental CHL impairs both within- and across-frequency processing and provide behavioral evidence that CNS mechanisms are affected by a peripheral hearing impairment.

We used the rat primary auditory cortex (A1) as a model to probe the effects of cholinergic enhancement on perceptual learning and auditory processing mechanisms in both young and old animals. Rats learned to perform a two-tone frequency discrimination task over the course of two weeks, combined with either the administration of a cholinesterase inhibitor or saline. We found that while both age groups learned the task more quickly through cholinergic enhancement, the young did so by improving target detection, whereas the old did so by inhibiting erroneous responses to nontarget stimuli. We also found that cholinergic enhancement led to marked functional and structural changes within A1 in both young and old rats. Importantly, we found that several functional changes observed in the old rats, particularly those relating to the processing and inhibition of nontargets, produced cortical processing features that resembled those of young untrained rats more so than those of older adult rats. Overall, these findings demonstrate that combining auditory training with neuromodulation of the cholinergic system can restore many of the auditory cortical functional deficits observed as a result of normal aging and add to the growing body of evidence demonstrating that many age-related perceptual and neuroplastic changes are reversible.

Significance Complex pitch perception serves a pivotal role in human audition, especially in speech and music perception. It has been suggested that pitch perception mechanisms demonstrated in humans are not shared by nonhuman species. Here we provide evidence that a New World monkey, the common marmoset, shares all primary features of complex pitch perception mechanisms with humans. Combined with previous findings of a specialized pitch processing region in both marmoset and human auditory cortex, this evidence suggests that pitch perception mechanisms likely originated early in primate evolution.

Poorer hearing in the presence of background noise is a significant problem for the hearing impaired. Ototoxic drugs, ageing, and noise exposure can damage the sensory hair cells of the inner ear that are essential for normal hearing sensitivity. The relationship between outer hair cell (OHC) loss and progressively poorer hearing sensitivity in quiet or in competing background noise is supported by a number of human and animal studies. In contrast, the effect of moderate inner hair cell (IHC) loss or dysfunction shows almost no impact on behavioral measures of hearing sensitivity in quiet, when OHCs remain intact, but the relationship between selective IHC loss and hearing in noise remains relatively unknown. Here, a moderately high dose of carboplatin (75 mg/kg) that produced IHC loss in chinchillas ranging from 40 to 80 % had little effect on thresholds in quiet. However, when tested in the presence of competing broadband (BBN) or narrowband noise (NBN), thresholds increased significantly. IHC loss >60 % increased signal-to-noise ratios (SNRs) for tones (500-11,300 Hz) in competing BBN by 5-10 dB and broadened the masking function under NBN. These data suggest that IHC loss or dysfunction may play a significant role in listening in noise independent of OHC integrity and that these deficits may be present even when thresholds in quiet are within normal limits.

Persistent activity has been reported in many brain areas and is hypothesized to mediate working memory and emotional brain states and to rely upon network or biophysical feedback. Here, we demonstrate a novel mechanism by which persistent neuronal activity can be generated without feedback, relying instead on the slow removal of Na+ from neurons following bursts of activity. We show that mitral cells in the accessory olfactory bulb (AOB), which plays a major role in mammalian social behavior, may respond to a brief sensory stimulation with persistent firing. By combining electrical recordings, Ca2+ and Na+ imaging, and realistic computational modeling, we explored the mechanisms underlying the persistent activity in AOB mitral cells. We found that the exceptionally slow inward current that underlies this activity is governed by prolonged dynamics of intracellular Na+ ([Na+]i), which affects neuronal electrical activity via several pathways. Specifically, elevated dendritic [Na+]i reverses the Na+-Ca2+ exchanger activity, thus modifying the [Ca2+]i set-point. This process, which relies on ubiquitous membrane mechanisms, is likely to play a role in other neuronal types in various brain regions.

The locust visual system contains a well-defined motion-sensitive pathway that transfers visual input to motor centers involved in predator evasion and collision avoidance. One interneuron in this pathway, the descending contralateral movement detector (DCMD), is typically described as using rate coding; edge expansion of approaching objects causes an increased rate of neuronal firing that peaks after a certain retinal threshold angle is exceeded. However, evidence of intrinsic DCMD bursting properties combined with observable oscillations in mean firing rates and tight clustering of spikes in raw traces, suggest that bursting may be important for motion detection. Sensory neuron bursting provides important timing information about dynamic stimuli in many model systems, yet no studies have rigorously investigated if bursting occurs in the locust DCMD during object approach. We presented repetitions of 30 looming stimuli known to generate behavioral responses to each of 20 locusts in order to identify and quantify putative bursting activity in the DCMD. Overall, we found a bimodal distribution of inter-spike intervals (ISI) with peaks of more frequent and shorter ISIs occurring from 1-8 ms and longer less frequent ISIs occurring from 40-50 ms. Subsequent analysis identified bursts and isolated single spikes from the responses. Bursting frequency increased in the latter phase of an approach and peaked at the time of collision, while isolated spiking was predominant during the beginning of stimulus approach. We also found that the majority of inter-burst intervals (IBIs) occurred at 40-50 ms (or 20-25 bursts/s). Bursting also occurred across varied stimulus parameters and suggests that burst timing may be a key component of looming detection. Our findings suggest that the DCMD uses two modes of coding to transmit information about looming stimuli and that these modes change dynamically with a changing stimulus at a behaviorally-relevant time.

Earlier studies demonstrate that when the frequency of rhythmic tone sequences or streams is task relevant, ongoing excitability fluctuations (oscillations) of neuronal ensembles in primary auditory cortex (A1) entrain to stimulation in a frequency dependent way that sharpens frequency tuning. The phase distribution across A1 neuronal ensembles at time points when attended stimuli are predicted to occur reflects the focus of attention along the spectral attribute of auditory stimuli. This study examined how neuronal activity is modulated if only the temporal features of rhythmic stimulus streams are relevant. We presented macaques with auditory clicks arranged in 33 Hz (gamma timescale) quintets, repeated at a 1.6 Hz (delta timescale) rate. Such multi-scale, hierarchically organized temporal structure is characteristic of vocalizations and other natural stimuli. Monkeys were required to detect and respond to deviations in the temporal pattern of gamma quintets. As expected, engagement in the auditory task resulted in the multi-scale entrainment of delta- and gamma-band neuronal oscillations across all of A1. Surprisingly, however, the phase-alignment, and thus, the physiological impact of entrainment differed across the tonotopic map in A1. In the region of 11-16 kHz representation, entrainment most often aligned high excitability oscillatory phases with task-relevant events in the input stream and thus resulted in response enhancement. In the remainder of the A1 sites, entrainment generally resulted in response suppression. Our data indicate that the suppressive effects were due to low excitability phase delta oscillatory entrainment and the phase amplitude coupling of delta and gamma oscillations. Regardless of the phase or frequency, entrainment appeared stronger in left A1, indicative of the hemispheric lateralization of auditory function.

Although central serotonergic systems are known to influence responses to noxious stimuli, mechanisms underlying serotonergic modulation of pain responses are unclear. We proposed that serotonin 2C receptors (5-HT2CRs), which are expressed within brain regions implicated in sensory and affective responses to pain, contribute to the serotonergic modulation of pain responses. In mice constitutively lacking 5-HT2CRs (2CKO mice) we found normal baseline sensory responses to noxious thermal, mechanical and chemical stimuli. In contrast, 2CKO mice exhibited a selective enhancement of affect-related ultrasonic afterdischarge vocalizations in response to footshock. Enhanced affect-related responses to noxious stimuli were also exhibited by 2CKO mice in a fear-sensitized startle assay. The extent to which a brief series of unconditioned footshocks produced enhancement of acoustic startle responses was markedly increased in 2CKO mice. As mesolimbic dopamine pathways influence affective responses to noxious stimuli, and these pathways are disinhibited in 2CKO mice, we examined the sensitivity of footshock-induced enhancement of startle to dopamine receptor blockade. Systemic administration of the dopamine D2/D3 receptor antagonist raclopride selectively reduced footshock-induced enhancement of startle without influencing baseline acoustic startle responses. We propose that 5-HT2CRs regulate affective behavioral responses to unconditioned aversive stimuli through mechanisms involving the disinhibition of ascending dopaminergic pathways.

The ability to discriminate tones of different frequencies is fundamentally important for everyday hearing. While neurons in the primary auditory cortex (AC) respond differentially to tones of different frequencies, whether and how AC regulates auditory behaviors that rely on frequency discrimination remains poorly understood. Here, we find that the level of activity of inhibitory neurons in AC controls frequency specificity in innate and learned auditory behaviors that rely on frequency discrimination. Photoactivation of parvalbumin-positive interneurons (PVs) improved the ability of the mouse to detect a shift in tone frequency, whereas photosuppression of PVs impaired the performance. Furthermore, photosuppression of PVs during discriminative auditory fear conditioning increased generalization of conditioned response across tone frequencies, whereas PV photoactivation preserved normal specificity of learning. The observed changes in behavioral performance were correlated with bidirectional changes in the magnitude of tone-evoked responses, consistent with predictions of a model of a coupled excitatory-inhibitory cortical network. Direct photoactivation of excitatory neurons, which did not change tone-evoked response magnitude, did not affect behavioral performance in either task. Our results identify a new function for inhibition in the auditory cortex, demonstrating that it can improve or impair acuity of innate and learned auditory behaviors that rely on frequency discrimination.

Primary sensory cortical fields develop highly specific associative representational plasticity, notably enlarged area of representation of reinforced signal stimuli within their topographic maps. However, overtraining subjects after they have solved an instrumental task can reduce or eliminate the expansion while the successful behavior remains. As the development of this plasticity depends on the learning strategy used to solve a task, we asked whether the loss of expansion is due to the strategy used during overtraining. Adult male rats were trained in a three-tone auditory discrimination task to bar-press to the CS+ for water reward and refrain from doing so during the CS- tones and silent intertrial intervals; errors were punished by a flashing light and time-out penalty. Groups acquired this task to a criterion within seven training sessions by relying on a strategy that was "bar-press from tone-onset-to-error signal" ("TOTE"). Three groups then received different levels of overtraining: Group ST, none; Group RT, one week; Group OT, three weeks. Post-training mapping of their primary auditory fields (A1) showed that Groups ST and RT had developed significantly expanded representational areas, specifically restricted to the frequency band of the CS+ tone. In contrast, the A1 of Group OT was no different from naïve controls. Analysis of learning strategy revealed this group had shifted strategy to a refinement of TOTE in which they self-terminated bar-presses before making an error ("iTOTE"). Across all animals, the greater the use of iTOTE, the smaller was the representation of the CS+ in A1. Thus, the loss of cortical expansion is attributable to a shift or refinement in strategy. This reversal of expansion was considered in light of a novel theoretical framework (CONCERTO) highlighting four basic principles of brain function that resolve anomalous findings and explaining why even a minor change in strategy would involve concomitant shifts of involved brain sites, including reversal of cortical expansion.

Three decades of electrophysiological research on cerebellar cortical activity underlying Pavlovian conditioning have expanded our understanding of motor learning in the brain. Purkinje cell simple spike suppression is considered to be crucial in the expression of conditional blink responses (CRs). However, trial-by-trial quantification of this link in awake behaving animals is lacking, and current hypotheses regarding the underlying plasticity mechanisms have diverged from the classical parallel fiber one to the Purkinje cell synapse LTD hypothesis. Here, we establish that acquired simple spike suppression, acquired conditioned stimulus (CS)-related complex spike responses, and molecular layer interneuron (MLI) activity predict the expression of CRs on a trial-by-trial basis using awake behaving mice. Additionally, we show that two independent transgenic mouse mutants with impaired MLI function exhibit motor learning deficits. Our findings suggest multiple cerebellar cortical plasticity mechanisms underlying simple spike suppression, and they implicate the broader involvement of the olivocerebellar module within the interstimulus interval.

Autism is a neurodevelopmental disorder clinically characterized by deficits in communication, lack of social interaction and repetitive behaviors with restricted interests. A number of studies have reported that sensory perception abnormalities are common in autistic individuals and might contribute to the complex behavioral symptoms of the disorder. In this context, hearing incongruence is particularly prevalent. Considering that some of this abnormal processing might stem from the unbalance of inhibitory and excitatory drives in brain circuitries, we used an animal model of autism induced by valproic acid (VPA) during pregnancy in order to investigate the tonotopic organization of the primary auditory cortex (AI) and its local inhibitory circuitry. Our results show that VPA rats have distorted primary auditory maps with over-representation of high frequencies, broadly tuned receptive fields and higher sound intensity thresholds as compared to controls. However, we did not detect differences in the number of parvalbumin-positive interneurons in AI of VPA and control rats. Altogether our findings show that neurophysiological impairments of hearing perception in this autism model occur independently of alterations in the number of parvalbumin-expressing interneurons. These data support the notion that fine circuit alterations, rather than gross cellular modification, could lead to neurophysiological changes in the autistic brain.

Individuals with Rett syndrome have greatly impaired speech and language abilities. Auditory brainstem responses to sounds are normal, but cortical responses are highly abnormal. In this study, we used the novel rat Mecp2 knockout model of Rett syndrome to document the neural and behavioral processing of speech sounds. We hypothesized that both speech discrimination ability and the neural response to speech sounds would be impaired in Mecp2 rats. We expected that extensive speech training would improve speech discrimination ability and the cortical response to speech sounds. Our results reveal that speech responses across all four auditory cortex fields of Mecp2 rats were hyperexcitable, responded slower, and were less able to follow rapidly presented sounds. While Mecp2 rats could accurately perform consonant and vowel discrimination tasks in quiet, they were significantly impaired at speech sound discrimination in background noise. Extensive speech training improved discrimination ability. Training shifted cortical responses in both Mecp2 and control rats to favor the onset of speech sounds. While training increased the response to low frequency sounds in control rats, the opposite occurred in Mecp2 rats. Although neural coding and plasticity are abnormal in the rat model of Rett syndrome, extensive therapy appears to be effective. These findings may help to explain some aspects of communication deficits in Rett syndrome and suggest that extensive rehabilitation therapy might prove beneficial.

Objective: Using the Medtronic Activa® PC + S system, this study investigated how passive joint manipulation, reaching behavior, and deep brain stimulation (DBS) modulate local field potential (LFP) activity in the subthalamic nucleus (STN) and globus pallidus (GP). Approach: Five non-human primates were implanted unilaterally with one or more DBS leads. LFPs were collected in montage recordings during resting state conditions and during motor tasks that facilitate the expression of parkinsonian motor signs. These recordings were made in the naïve state in one subject, in the parkinsonian state in two subjects, and in both naïve and parkinsonian states in two subjects. Main results: LFPs measured at rest were consistent over time for a given recording location and parkinsonian state in a given subject; however, LFPs were highly variable between subjects, between and within recording locations, and across parkinsonian states. LFPs in both naïve and parkinsonian states across all recorded nuclei contained a spectral peak in the beta band (10-30 Hz). Moreover, the spectral content of recorded LFPs was modulated by passive and active movement of the subjects' limbs. LFPs recorded during a cued-reaching task displayed task-related beta desynchronization in STN and GP. The bidirectional capabilities of the Activa® PC + S also allowed for recording LFPs while delivering DBS. The therapeutic effect of STN DBS on parkinsonian rigidity outlasted stimulation for 30-60 s, but there was no correlation with beta band power. Significance: This study emphasizes (1) the variability in spontaneous LFPs amongst subjects and (2) the value of using the Activa® PC + S system to record neural data in the context of behavioral tasks that allow one to evaluate a subject's symptomatology.

How the brain selects appropriate sensory inputs and suppresses distractors is unknown. Given the well-established role of the prefrontal cortex (PFC) in executive function, its interactions with sensory cortical areas during attention have been hypothesized to control sensory selection. To test this idea and, more generally, dissect the circuits underlying sensory selection, we developed a cross-modal divided-attention task in mice that allowed genetic access to this cognitive process. By optogenetically perturbing PFC function in a temporally precise window, the ability of mice to select appropriately between conflicting visual and auditory stimuli was diminished. Equivalent sensory thalamocortical manipulations showed that behaviour was causally dependent on PFC interactions with the sensory thalamus, not sensory cortex. Consistent with this notion, we found neurons of the visual thalamic reticular nucleus (visTRN) to exhibit PFC-dependent changes in firing rate predictive of the modality selected. visTRN activity was causal to performance as confirmed by bidirectional optogenetic manipulations of this subnetwork. Using a combination of electrophysiology and intracellular chloride photometry, we demonstrated that visTRN dynamically controls visual thalamic gain through feedforward inhibition. Our experiments introduce a new subcortical model of sensory selection, in which the PFC biases thalamic reticular subnetworks to control thalamic sensory gain, selecting appropriate inputs for further processing.

The lateral amygdala (LA) acquires differential coding of predictive and non-predictive fear stimuli that is critical for proper fear memory assignment. The neurotransmitter dopamine is an important modulator of LA activity and facilitates fear memory formation, but whether dopamine neurons aid in the establishment of discriminative fear coding by the LA is unknown. NMDA-type glutamate receptors in dopamine neurons are critical for the prevention of generalized fear following an aversive experience, suggesting a potential link between a cell autonomous function of NMDAR in dopamine neurons and fear coding by the LA. Here, we utilized mice with a selective genetic inactivation functional NMDARs in dopamine neurons (DAT-NR1 KO mice) combined with behavior, in vivo electrophysiology, and ex vivo electrophysiology in LA neurons to demonstrate that plasticity underlying differential fear coding in the LA is regulated by NMDAR signaling in dopamine neurons and alterations in this plasticity is associated non-discriminative cued-fear responses.

In Parkinson's disease patients in the OFF medication state, basal ganglia local field potentials exhibit changes in beta and gamma oscillations that correlate with reduced voluntary movement, manifested as rigidity and akinesia. However, magnetoencephalography and low-resolution electrocorticography (ECoG) studies in Parkinson's patients suggest that changes in sensorimotor cortical oscillations differ from those of the basal ganglia. To more clearly define the role of sensorimotor cortex oscillatory activity in Parkinson's, we performed intraoperative, high-resolution (4 mm spacing) ECoG recordings in 10 Parkinson's patients (2 females, ages 47-72) undergoing deep brain stimulation (DBS) lead placement in the awake, OFF medication state. We analyzed ECoG potentials during a computer-controlled reaching task designed to separate movement preparation from movement execution and compared findings to similar invasive recordings in eight patients with essential tremor (3 females, ages 59-78), a condition not associated with rigidity or akinesia. We show that (1) cortical beta spectral power at rest does not differ between Parkinson's and essential tremor patients (p = 0.85), (2) early motor preparation in Parkinson's patients in the OFF medication state is associated with a larger beta desynchronization compared to patients with essential tremor (p = 0.0061), and (3) cortical broadband gamma power is elevated in Parkinson's patients compared to essential tremor patients during both rest and task recordings (p = 0.004). Our findings suggest an oscillatory profile in sensorimotor cortex of Parkinson's patients that, in contrast to the basal ganglia, may act to promote movement to oppose the anti-kinetic bias of the dopamine-depleted state.

Despite many prior studies demonstrating offline behavioral gains in motor skills after sleep, the underlying neural mechanisms remain poorly understood. To investigate the neurophysiological basis for offline gains, we performed single-unit recordings in motor cortex as rats learned a skilled upper-limb task. We found that sleep improved movement speed with preservation of accuracy. These offline improvements were linked to both replay of task-related ensembles during non-rapid eye movement (NREM) sleep and temporal shifts that more tightly bound motor cortical ensembles to movements; such offline gains and temporal shifts were not evident with sleep restriction. Interestingly, replay was linked to the coincidence of slow-wave events and bursts of spindle activity. Neurons that experienced the most consistent replay also underwent the most significant temporal shift and binding to the motor task. Significantly, replay and the associated performance gains after sleep only occurred when animals first learned the skill; continued practice during later stages of learning (i.e., after motor kinematics had stabilized) did not show evidence of replay. Our results highlight how replay of synchronous neural activity during sleep mediates large-scale neural plasticity and stabilizes kinematics during early motor learning.