Behavioral Neuroscience publications

The mechanisms by which functional maps and map plasticity contribute to cortical computation remain controversial. Recent studies have revisited the theory of neural Darwinism to interpret the learning-induced map plasticity and neuronal heterogeneity observed in the cortex. Here, we hypothesize that the Darwinian principle provides a substrate to explain the relationship between neuron heterogeneity and cortical functional maps. We demonstrate in the rat auditory cortex that the degree of response variance is closely correlated with the size of its representational area. Further, we show that the response variance within a given population is altered through training. These results suggest that larger representational areas may help to accommodate heterogeneous populations of neurons. Thus, functional maps and map plasticity are likely to play essential roles in Darwinian computation, serving as effective, but not absolutely necessary, structures to generate diverse response properties within a neural population.

In recordings from anterior piriform cortex in awake behaving mice, we found that neuronal firing early in the olfactory pathway simultaneously conveyed fundamentally different information: odor value (is the odor rewarded?) and identity (what is the smell?). Thus, this sensory system performs early multiplexing of information reflecting stimulus-specific characteristics with that used for decision-making.

Many natural sounds are periodic and consist of frequencies (harmonics) that are integer multiples of a common fundamental frequency (F0). Such harmonic complex tones (HCTs) evoke a pitch corresponding to their F0, which plays a key role in the perception of speech and music. "Pitch-selective" neurons have been identified in non-primary auditory cortex of marmoset monkeys. Noninvasive studies point to a putative "pitch center" located in a homologous cortical region in humans. It remains unclear whether there is sufficient spectral and temporal information available at the level of primary auditory cortex (A1) to enable reliable pitch extraction in non-primary auditory cortex. Here we evaluated multiunit responses to HCTs in A1 of awake macaques using a stimulus design employed in auditory nerve studies of pitch encoding. The F0 of the HCTs was varied in small increments, such that harmonics of the HCTs fell either on the peak or on the sides of the neuronal pure tone tuning functions. Resultant response-amplitude-versus-harmonic-number functions ("rate-place profiles") displayed a periodic pattern reflecting the neuronal representation of individual HCT harmonics. Consistent with psychoacoustic findings in humans, lower harmonics were better resolved in rate-place profiles than higher harmonics. Lower F0s were also temporally represented by neuronal phase-locking to the periodic waveform of the HCTs. Findings indicate that population responses in A1 contain sufficient spectral and temporal information for extracting the pitch of HCTs by neurons in downstream cortical areas that receive their input from A1.

Damage to the medial temporal lobe impairs the encoding of new memories and the retrieval of memories acquired immediately before the damage in human. In this study, we demonstrated that artificial visuoauditory memory traces can be established in the rat auditory cortex and that their encoding and retrieval depend on the entorhinal cortex of the medial temporal lobe in the rat. We trained rats to associate a visual stimulus with electrical stimulation of the auditory cortex using a classical conditioning protocol. After conditioning, we examined the associative memory traces electrophysiologically (i.e., visual stimulus-evoked responses of auditory cortical neurons) and behaviorally (i.e., visual stimulus-induced freezing and visual stimulus-guided reward retrieval). The establishment of a visuoauditory memory trace in the auditory cortex, which was detectable by electrophysiological recordings, was achieved over 20-30 conditioning trials and was blocked by unilateral, temporary inactivation of the entorhinal cortex. Retrieval of a previously established visuoauditory memory was also affected by unilateral entorhinal cortex inactivation. These findings suggest that the entorhinal cortex is necessary for the encoding and involved in the retrieval of artificial visuoauditory memory in the auditory cortex, at least during the early stages of memory consolidation.

Amplitude modulation encoding is critical for human speech perception and complex sound processing in general. The modulation transfer function (MTF) is a staple of auditory psychophysics, and has been shown to predict speech intelligibility performance in a range of adverse listening conditions and hearing impairments, including cochlear implant-supported hearing. Although both tonal and broadband carriers have been used in psychophysical studies of modulation detection and discrimination, relatively little is known about differences in the cortical representation of such signals. We obtained MTFs in response to sinusoidal amplitude modulation (SAM) for both narrowband tonal carriers and two-octave bandwidth noise carriers in the auditory core of awake squirrel monkeys. MTFs spanning modulation frequencies from 4 to 512 Hz were obtained using 16 channel linear recording arrays sampling across all cortical laminae. Carrier frequency for tonal SAM and center frequency for noise SAM was set at the estimated BF for each penetration. Changes in carrier type affected both rate and temporal MTFs in many neurons. Using spike discrimination techniques, we found that discrimination of modulation frequency was significantly better for tonal SAM than for noise SAM, though the differences were modest at the population level. Moreover, spike trains elicited by tonal and noise SAM could be readily discriminated in most cases. Collectively, our results reveal remarkable sensitivity to the spectral content of modulated signals, and indicate substantial interdependence between temporal and spectral processing in neurons of the core auditory cortex.

Pitch is one of the most fundamental percepts in the auditory system and can be extracted using either spectral or temporal information in an acoustic signal. Although pitch perception has been extensively studied in human subjects, it is far less clear how nonhuman primates perceive pitch. We have addressed this question in a series of behavioral studies in which marmosets, a vocal nonhuman primate species, were trained to discriminate complex harmonic tones differing in either spectral (fundamental frequency [f 0 ]) or temporal envelope (repetition rate) cues. We found that marmosets used temporal envelope information to discriminate pitch for acoustic stimuli with higher-order harmonics and lower f 0 values and spectral information for acoustic stimuli with lower-order harmonics and higher f 0 values. We further measured frequency resolution in marmosets using a psychophysical task in which pure tone thresholds were measured as a function of notched noise masker bandwidth. Results show that only the first four harmonics are resolved at low f 0 values and up to 16 harmonics are resolved at higher f 0 values. Resolvability in marmosets is different from that in humans, where the first five to nine harmonics are consistently resolved across most f 0 values, and is likely the result of a smaller marmoset cochlea. In sum, these results show that marmosets use two mechanisms to extract pitch (harmonic templates [spectral] for resolved harmonics, and envelope extraction [temporal] for unresolved harmonics) and that species differences in stimulus resolvability need to be taken into account when investigating and comparing mechanisms of pitch perception across animals.

Stimuli associated with high rewards evoke stronger neuronal activity than stimuli associated with lower rewards in many brain regions. It is not well understood how these reward effects influence activity in sensory cortices that represent low-level stimulus features. Here, we investigated the effects of reward information in the primary visual cortex (area V1) of monkeys. We found that the reward value of a stimulus relative to the value of other stimuli is a good predictor of V1 activity. Relative value biases the competition between stimuli, just as has been shown for selective attention. The neuronal latency of this reward value effect in V1 was similar to the latency of attentional influences. Moreover, V1 neurons with a strong value effect also exhibited a strong attention effect, which implies that relative value and top–down attention engage overlapping, if not identical, neuronal selection mechanisms. Our findings demonstrate that the effects of reward value reach down to the earliest sensory processing levels of the cerebral cortex and imply that theories about the effects of reward coding and top–down attention on visual representations should be unified.

Animals are thought to evaluate the desirability of action options using a unified scale that combines predicted benefits (“rewards”), costs, and the animal's internal motivational state. Midbrain dopamine neurons have long been associated with the reward part of this equation, but it is unclear whether these neurons also estimate the costs of taking an action. We studied the spiking activity of dopamine neurons in the substantia nigra pars compacta of monkeys ( Macaca mulatta ) during a reaching task in which the energetic costs incurred (friction loads) and the benefits gained (drops of food) were manipulated independently. Although the majority of dopamine neurons encoded the upcoming reward alone, a subset predicted net utility of a course of action by signaling the expected reward magnitude discounted by the invested cost in terms of physical effort. In addition, the tonic activity of some dopamine neurons was slowly reduced in conjunction with the accumulated trials, which is consistent with the hypothesized role for tonic dopamine in the invigoration or motivation of instrumental responding. The present results shed light on an often-hypothesized role for dopamine in the regulation of the balance in natural behaviors between the energy expended and the benefits gained, which could explain why dopamine disorders, such as Parkinson's disease, lead to a breakdown of that balance.

Neural representation in the auditory cortex is rapidly modulated by both top-down attention and bottom-up stimulus properties, in order to improve perception in a given context. Learning-induced, pre-attentive, map plasticity has been also studied in the anesthetized cortex; however, little attention has been paid to rapid, context-dependent modulation. We hypothesize that context-specific learning leads to pre-attentively modulated, multiplex representation in the auditory cortex. Here, we investigate map plasticity in the auditory cortices of anesthetized rats conditioned in a context-dependent manner, such that a conditioned stimulus (CS) of a 20-kHz tone and an unconditioned stimulus (US) of a mild electrical shock were associated only under a noisy auditory context, but not in silence. After the conditioning, although no distinct plasticity was found in the tonotopic map, tone-evoked responses were more noise-resistive than pre-conditioning. Yet, the conditioned group showed a reduced spread of activation to each tone with noise, but not with silence, associated with a sharpening of frequency tuning. The encoding accuracy index of neurons showed that conditioning deteriorated the accuracy of tone-frequency representations in noisy condition at off-CS regions, but not at CS regions, suggesting that arbitrary tones around the frequency of the CS were more likely perceived as the CS in a specific context, where CS was associated with US. These results together demonstrate that learning-induced plasticity in the auditory cortex occurs in a context-dependent manner.

Claustrophobia, the well-known fear of being trapped in narrow/closed spaces, is often considered a conditioned response to traumatic experience. Surprisingly, we found that mutations affecting a single gene, encoding a stress-regulated neuronal protein, can cause claustrophobia. Gpm6a-deficient mice develop normally and lack obvious behavioral abnormalities. However, when mildly stressed by single-housing, these mice develop a striking claustrophobia-like phenotype, which is not inducible in wild-type controls, even by severe stress. The human GPM6A gene is located on chromosome 4q32-q34, a region linked to panic disorder. Sequence analysis of 115 claustrophobic and non-claustrophobic subjects identified nine variants in the noncoding region of the gene that are more frequent in affected individuals (P=0.028). One variant in the 3'untranslated region was linked to claustrophobia in two small pedigrees. This mutant mRNA is functional but cannot be silenced by neuronal miR124 derived itself from a stress-regulated transcript. We suggest that loosing dynamic regulation of neuronal GPM6A expression poses a genetic risk for claustrophobia.

Although the ferret has become an important model species for studying both fundamental and clinical aspects of spatial hearing, previous behavioral work has focused on studies of sound localization and spatial release from masking in the free field. This makes it difficult to tease apart the role played by different spatial cues. In humans and other species, interaural time differences (ITDs) and interaural level differences (ILDs) play a critical role in sound localization in the azimuthal plane and also facilitate sound source separation in noisy environments. In this study, we used a range of broadband noise stimuli presented via customized earphones to measure ITD and ILD sensitivity in the ferret. Our behavioral data show that ferrets are extremely sensitive to changes in either binaural cue, with levels of performance approximating that found in humans. The measured thresholds were relatively stable despite extensive and prolonged (>16 weeks) testing on ITD and ILD tasks with broadband stimuli. For both cues, sensitivity was reduced at shorter durations. In addition, subtle effects of changing the stimulus envelope were observed on ITD, but not ILD, thresholds. Sensitivity to these cues also differed in other ways. Whereas ILD sensitivity was unaffected by changes in average binaural level or interaural correlation, the same manipulations produced much larger effects on ITD sensitivity, with thresholds declining when either of these parameters was reduced. The binaural sensitivity measured in this study can largely account for the ability of ferrets to localize broadband stimuli in the azimuthal plane. Our results are also broadly consistent with data from humans and confirm the ferret as an excellent experimental model for studying spatial hearing.

The nucleus basalis (NB) in the basal forebrain provides most of the cholinergic input to the neocortex and has been implicated in a variety of cognitive functions related to the processing of sensory stimuli. However, the role that cortical acetylcholine release plays in perception remains unclear. Here we show that selective loss of cholinergic NB neurons that project to the cortex reduces the accuracy with which ferrets localize brief sounds and prevents them from adaptively reweighting auditory localization cues in response to chronic occlusion of one ear. Cholinergic input to the cortex was disrupted by making bilateral injections of the immunotoxin ME20.4-SAP into the NB. This produced a substantial loss of both p75 neurotrophin receptor (p75 NTR )-positive and choline acetyltransferase-positive cells in this region and of acetylcholinesterase-positive fibers throughout the auditory cortex. These animals were significantly impaired in their ability to localize short broadband sounds (40–500 ms in duration) in the horizontal plane, with larger cholinergic cell lesions producing greater performance impairments. Although they localized longer sounds with normal accuracy, their response times were significantly longer than controls. Ferrets with cholinergic forebrain lesions were also less able to relearn to localize sound after plugging one ear. In contrast to controls, they exhibited little recovery of localization performance after behavioral training. Together, these results show that cortical cholinergic inputs contribute to the perception of sound source location under normal hearing conditions and play a critical role in allowing the auditory system to adapt to changes in the spatial cues available.

Learning alters the responses of neurons in the neocortex, typically strengthening their encoding of behaviorally relevant stimuli. These enhancements are studied extensively in the auditory cortex by characterizing changes in firing rates and evoked potentials. However, synchronous activity is also important for the processing of stimuli, especially the relationship between gamma oscillations in the local field potential and spiking. We investigated whether tone/shock fear conditioning in rats, a task known to alter responses in auditory cortex, also modified the relationship between gamma and unit activity. A boost in gamma oscillations developed, especially at sites tuned near the tone, and strengthened across multiple conditioning sessions. Unit activity became increasingly phase-locked to gamma, with sites tuned near the tone developing enhanced phase-locking during the tone, whereas those tuned away maintained a tendency to decrease their phase-locking. Enhancements in the coordination of spiking between sites tuned near the tone developed within the first conditioning session and remained throughout the rest of training. Enhanced cross-covariances in unit activity were strongest for subjects that exhibited robust conditioned fear. These results illustrate that changes in sensory cortex during associative learning extend to the coordination of neurons encoding the relevant stimulus, with implications for how it is processed downstream.

Auditory-cued behavioral training can alter neural circuits in primary auditory cortex (A1), but the mechanisms and consequences of experience-dependent cortical plasticity are not fully understood. To address this issue, we trained adult rats to detect a 5 kHz target in order to receive a food reward. After 14 days training we identified three locations within A1: (i) the region representing the characteristic frequency (CF) 5 kHz, (ii) a nearby region with CF ∼10 kHz, and (iii) a more distant region with CF ∼20 kHz. In order to compare functional connectivity in A1 near to, vs. far from, the representation of the target frequency, we placed a 16-channel multiprobe in middle- (∼10 kHz) and high- (∼20 kHz) CF regions and obtained current-source density (CSD) profiles evoked by a range of tone stimuli (CF±1-3 octaves in quarter-octave steps). Our aim was to construct "CSD receptive fields" (CSD RFs) in order to determine the laminar and spectral profile of tone-evoked current sinks, and infer changes to thalamocortical and intracortical inputs. Behavioral training altered CSD RFs at the 10 kHz, but not 20 kHz, site relative to CSD RFs in untrained control animals. At the 10 kHz site, current sinks evoked by the target frequency were enhanced in layer 2/3, but the initial current sink in layer 4 was not altered. The results imply training-induced plasticity along intracortical pathways connecting the target representation with nearby cortical regions. Finally, we related behavioral performance (sensitivity index, d') to CSD responses in individual animals, and found a significant correlation between the development of d' over training and the amplitude of the target-evoked current sink in layer 2/3. The results suggest that plasticity along intracortical pathways is important for auditory learning.

Individuals with terminal and interstitial deletions of chromosome 1p36 have a spectrum of defects that includes eye anomalies, postnatal growth deficiency, structural brain anomalies, seizures, cognitive impairment, delayed motor development, behavior problems, hearing loss, cardiovascular malformations, cardiomyopathy, and renal anomalies. The proximal 1p36 genes that contribute to these defects have not been clearly delineated. The arginine-glutamic acid dipeptide (RE) repeats gene (RERE) is located in this region and encodes a nuclear receptor coregulator that plays a critical role in embryonic development as a positive regulator of retinoic acid signaling. Rere-null mice die of cardiac failure between E9.5 and E11.5. This limits their usefulness in studying the role of RERE in the latter stages of development and into adulthood. To overcome this limitation, we created an allelic series of RERE-deficient mice using an Rere-null allele, om, and a novel hypomorphic Rere allele, eyes3 (c.578T>C, p.Val193Ala), which we identified in an N-ethyl-N-nitrosourea (ENU)-based screen for autosomal recessive phenotypes. Analyses of these mice revealed microphthalmia, postnatal growth deficiency, brain hypoplasia, decreased numbers of neuronal nuclear antigen (NeuN)-positive hippocampal neurons, hearing loss, cardiovascular malformations-aortic arch anomalies, double outlet right ventricle, and transposition of the great arteries, and perimembranous ventricular septal defects-spontaneous development of cardiac fibrosis and renal agenesis. These findings suggest that RERE plays a critical role in the development and function of multiple organs including the eye, brain, inner ear, heart and kidney. It follows that haploinsufficiency of RERE may contribute-alone or in conjunction with other genetic, environmental, or stochastic factors-to the development of many of the phenotypes seen in individuals with terminal and interstitial deletions that include the proximal region of chromosome 1p36.

In the auditory system of the big brown bat ( Eptesicus fuscus), paired conditioned tonal (CS) and unconditioned leg stimuli (US) for auditory fear conditioning elicit tone-specific plasticity represented by best-frequency (BF) shifts that are augmented by acetylcholine, whereas unpaired CS and US for pseudoconditioning elicit a small BF shift and prominent nonspecific plasticity at the same time. The latter represents the nonspecific augmentations of auditory responses accompanied by the broadening of frequency tuning and decrease in threshold. It is unknown which neuromodulators are important in evoking the nonspecific plasticity. We found that histamine (HA) and an HA3 receptor (HA3R) agonist (α-methyl-HA) decreased, but an HA3R antagonist (thioperamide) increased, cortical auditory responses; that the HA3R agonist applied to the primary auditory cortex before pseudoconditioning abolished the nonspecific augmentation in the cortex without affecting the small cortical BF shift; and that antagonists of acetylcholine, norepinephrine, dopamine, and serotonin receptors did not abolish the nonspecific augmentation elicited by pseudoconditioning. The histaminergic system plays an important role in eliciting the arousal and defensive behavior, possibly through nonspecific augmentation. Thus HA modulates the nonspecific augmentation, whereas acetylcholine amplifies the BF shifts. These two neuromodulators may mediate differential gating of cortical plasticity.

In 2006, Turner and colleagues (Behav. Neurosci., 120:188-195) introduced the gap-startle paradigm as a high-throughput method for tinnitus screening in rats. Under this paradigm, gap detection ability was assessed by determining the level of inhibition of the acoustic startle reflex produced by a short silent gap inserted in an otherwise continuous background sound prior to a loud startling stimulus. Animals with tinnitus were expected to show impaired gap detection ability (i.e., lack of inhibition of the acoustic startle reflex) if the background sound containing the gap was qualitatively similar to the tinnitus pitch. Thus, for the gap-startle paradigm to be a valid tool to screen for tinnitus, a robust startle response from which to inhibit must be present. Because recent studies have demonstrated that the acoustic startle reflex could be dramatically reduced following noise exposure, we endeavored to 1) modify the gap-startle paradigm to be more resilient in the presence of hearing loss, and 2) evaluate whether a reduction in startle reactivity could confound the interpretation of gap prepulse inhibition and lead to errors in screening for tinnitus. In the first experiment, the traditional broadband noise (BBN) startle stimulus was replaced by a bandpass noise in which the sound energy was concentrated in the lower frequencies (5-10 kHz) in order to maintain audibility of the startle stimulus after unilateral high-frequency noise exposure (16 kHz). However, rats still showed a 57% reduction in startle amplitude to the bandpass noise post-noise exposure. A follow-up experiment on a separate group of rats with transiently-induced conductive hearing loss revealed that startle reactivity was better preserved when the BBN startle stimulus was replaced by a rapid airpuff to the back of the rat's neck. Furthermore, it was found that transient unilateral conductive hearing loss, which was not likely to induce tinnitus, caused an impairment in gap prepulse inhibition as assessed with the traditional BBN gap-startle paradigm, resulting in a false-positive screening for tinnitus. Thus, the present study identifies significant caveats of the traditional gap-startle paradigm, and describes experimental parameters using an airpuff startle stimulus which may help to limit the negative consequences of reduced startle reactivity following noise exposure, thereby allowing researchers to better screen for tinnitus in animals with hearing loss.

Auditory neurons that exhibit stimulus-specific adaptation (SSA) decrease their response to common tones while retaining responsiveness to rare ones. We recorded single-unit responses from the inferior colliculus (IC) where SSA is known to occur and we explored for the first time SSA in the cochlear nucleus (CN) of rats. We assessed an important functional outcome of SSA, the extent to which frequency discriminability depends on sensory context. For this purpose, pure tones were presented in an oddball sequence as standard (high probability of occurrence) or deviant (low probability of occurrence) stimuli. To study frequency discriminability under different probability contexts, we varied the probability of occurrence and the frequency separation between tones. The neuronal sensitivity was estimated in terms of spike-count probability using signal detection theory. We reproduced the finding that many neurons in the IC exhibited SSA, but we did not observe significant SSA in our CN sample. We concluded that strong SSA is not a ubiquitous phenomenon in the CN. As predicted, frequency discriminability was enhanced in IC when stimuli were presented in an oddball context, and this enhancement was correlated with the degree of SSA shown by the neurons. In contrast, frequency discrimination by CN neurons was independent of stimulus context. Our results demonstrated that SSA is not widespread along the entire auditory pathway, and suggest that SSA increases frequency discriminability of single neurons beyond that expected from their tuning curves.

Subtle random deviations from perfect symmetry in bilateral traits are suggested to signal reduced phenotypic and genetic quality of a sender, but only little is known about the related receiver mechanisms for discriminating symmetrical from asymmetrical traits. Here we investigate these mechanisms in behavioural and neurophysiological experiments in the Mediterranean field cricket, Gryllus bimaculatus. A downward frequency modulation at the end of each syllable in the calling song has been suggested to indicate morphological asymmetry in sound radiating structures between left and right forewings. Even under ideal laboratory conditions on a trackball system female crickets only discriminated between songs of symmetrical and asymmetrical males in two-choice experiments at carrier frequencies of 4.4 kHz and large modulation depth of 600 and 800 Hz. Under these conditions they preferred the pure tone calling songs over the modulated (asymmetrical) alternative, whereas no preference was observed at carrier frequencies of 4.9 and 5.2 kHz. These preferences correlate well with responses of a pair of identified auditory interneuron (AN1), known for its importance in female phonotaxis. The interneuron is tuned to an average frequency of 4.9 kHz, and the roll-off towards lower and higher frequencies determines the magnitude of responses to pure tone and frequency modulated calling songs. The difference in response magnitude between the two neurons appears to drive the decision of females towards the song alternatives. We discuss the relevance of song differences based on asymmetry in the morphology of song producing structures under natural conditions.

Spectral timbre is an acoustic feature that enables human listeners to determine the identity of a spoken vowel. Despite its importance to sound perception, little is known about the neural representation of sound timbre and few psychophysical studies have investigated timbre discrimination in non-human species. In this study, ferrets were positively conditioned to discriminate artificial vowel sounds in a two-alternative-forced-choice paradigm. Animals quickly learned to discriminate the vowel sound /u/ from /ε/ and were immediately able to generalize across a range of voice pitches. They were further tested in a series of experiments designed to assess how well they could discriminate these vowel sounds under different listening conditions. First, a series of morphed vowels was created by systematically shifting the location of the first and second formant frequencies. Second, the ferrets were tested with single formant stimuli designed to assess which spectral cues they could be using to make their decisions. Finally, vowel discrimination thresholds were derived in the presence of noise maskers presented from either the same or a different spatial location. These data indicate that ferrets show robust vowel discrimination behavior across a range of listening conditions and that this ability shares many similarities with human listeners.