Synthesis of Hemispheric ITD Tuning from the Readout of a Neural Map: Commonalities of Proposed Coding Schemes in Birds and Mammals.

A major cue to infer sound direction is the difference in arrival time of the sound at the left and right ears, called interaural time difference (ITD). The neural coding of ITD and its similarity across species have been strongly debated. In the barn owl, an auditory specialist relying on sound localization to capture prey, ITDs within the physiological range determined by the head width are topographically represented at each frequency. The topographic representation suggests that sound direction may be inferred from the location of maximal neural activity within the map. Such topographical representation of ITD, however, is not evident in mammals. Instead, the preferred ITD of neurons in the mammalian brainstem often lies outside the physiological range and depends on the neuron's best frequency. Because of these disparities, it has been assumed that how spatial hearing is achieved in birds and mammals is fundamentally different. However, recent studies reveal ITD responses in the owl's forebrain and midbrain premotor area that are consistent with coding schemes proposed in mammals. Particularly, sound location in owls could be decoded from the relative firing rates of two broadly and inversely ITD-tuned channels. This evidence suggests that, at downstream stages, the code for ITD may not be qualitatively different across species. Thus, while experimental evidence continues to support the notion of differences in ITD representation across species and brain regions, the latest results indicate notable commonalities, suggesting that codes driving orienting behavior in mammals and birds may be comparable.

Emergence of an Adaptive Command for Orienting Behavior in Premotor Brainstem Neurons of Barn Owls.

The midbrain map of auditory space commands sound-orienting responses in barn owls. Owls precisely localize sounds in frontal space but underestimate the direction of peripheral sound sources. This bias for central locations was proposed to be adaptive to the decreased reliability in the periphery of sensory cues used for sound localization by the owl. Understanding the neural pathway supporting this biased behavior provides a means to address how adaptive motor commands are implemented by neurons. Here we find that the sensory input for sound direction is weighted by its reliability in premotor neurons of the midbrain tegmentum of owls (male and female), such that the mean population firing rate approximates the head-orienting behavior. We provide evidence that this coding may emerge through convergence of upstream projections from the midbrain map of auditory space. We further show that manipulating the sensory input yields changes predicted by the convergent network in both premotor neural responses and behavior. This work demonstrates how a topographic sensory representation can be linearly read out to adjust behavioral responses by the reliability of the sensory input.SIGNIFICANCE STATEMENT This research shows how statistics of the sensory input can be integrated into a behavioral command by readout of a sensory representation. The firing rate of midbrain premotor neurons receiving sensory information from a topographic representation of auditory space is weighted by the reliability of sensory cues. We show that these premotor responses are consistent with a weighted convergence from the topographic sensory representation. This convergence was also tested behaviorally, where manipulation of stimulus properties led to bidirectional changes in sound localization errors. Thus a topographic representation of auditory space is translated into a premotor command for sound localization that is modulated by sensory reliability.

Computational Analysis of Neonatal Mouse Ultrasonic Vocalization.

Neonatal vocalization is structurally altered in mouse models of autism spectrum disorder (ASD). Our published data showed that pup vocalization, under conditions of maternal separation, contains sequences whose alterations in a genetic mouse model of ASD impair social communication between pups and mothers. We describe details of a method which reveals the statistical structure of call sequences that are functionally critical for optimal maternal care. Entropy analysis determines the degree of non-random call sequencing. A Markov model determines the actual call sequences used by pups. Sparse partial least squares discriminant analysis (sPLS-DA) identifies call sequences that differentiate groups and reveals the degrees of individual variability in call sequences between groups. These three sets of analyses can be used to identify the otherwise hidden call structure that is altered in mouse models of developmental neuropsychiatric disorders, including not only autism but also schizophrenia. © 2018 by John Wiley & Sons, Inc.

Distinct Correlation Structure Supporting a Rate-Code for Sound Localization in the Owl's Auditory Forebrain.

While a topographic map of auditory space exists in the vertebrate midbrain, it is absent in the forebrain. Yet, both brain regions are implicated in sound localization. The heterogeneous spatial tuning of adjacent sites in the forebrain compared to the midbrain reflects different underlying circuitries, which is expected to affect the correlation structure, i.e., signal (similarity of tuning) and noise (trial-by-trial variability) correlations. Recent studies have drawn attention to the impact of response correlations on the information readout from a neural population. We thus analyzed the correlation structure in midbrain and forebrain regions of the barn owl's auditory system. Tetrodes were used to record in the midbrain and two forebrain regions, Field L and the downstream auditory arcopallium (AAr), in anesthetized owls. Nearby neurons in the midbrain showed high signal and noise correlations (R NC s), consistent with shared inputs. As previously reported, Field L was arranged in random clusters of similarly tuned neurons. Interestingly, AAr neurons displayed homogeneous monotonic azimuth tuning, while response variability of nearby neurons was significantly less correlated than the midbrain. Using a decoding approach, we demonstrate that low R NC in AAr restricts the potentially detrimental effect it can have on information, assuming a rate code proposed for mammalian sound localization. This study harnesses the power of correlation structure analysis to investigate the coding of auditory space. Our findings demonstrate distinct correlation structures in the auditory midbrain and forebrain, which would be beneficial for a rate-code framework for sound localization in the nontopographic forebrain representation of auditory space.

Methamphetamine-induced dopamine terminal deficits in the nucleus accumbens are exacerbated by reward-associated cues and attenuated by CB1 receptor antagonism.

Methamphetamine (METH) exposure is primarily associated with deleterious effects to dopaminergic neurons. While several studies have implicated the endocannabinoid system in METH's locomotor, rewarding and neurochemical effects, a role for this signaling system in METH's effects on dopamine terminal dynamics has not been elucidated. Given that CB1 receptor blockade reduces the acute potentiation of phasic extracellular dopamine release from other psychomotor stimulant drugs and that the degree of acute METH-induced increases in extracellular dopamine levels is related to the severity of dopamine depletion, we predicted that pretreatment with the CB1 receptor antagonist rimonabant would reduce METH-induced alterations at dopamine terminals. Furthermore, we hypothesized that administration of METH in environments where reward associated-cues were present would potentiate METH's acute effects on dopamine release in the nucleus accumbens and exacerbate changes in dopamine terminal activity. Fast-scan cyclic voltammetry was used to measure electrically-evoked dopamine release in the nucleus accumbens and revealed markers of compromised dopamine terminal integrity nine days after a single dose of METH. These were exacerbated in animals that received METH in the presence of reward-associated cues, and attenuated in rimonabant-pretreated animals. While these deficits in dopamine dynamics were associated with reduced operant responding on days following METH administration in animals treated with only METH, rimonabant-pretreated animals exhibited levels of operant responding comparable to control. Moreover, dopamine release correlated significantly with changes in lever pressing behavior that occurred on days following METH administration. Together these data suggest that the endocannabinoid system is involved in the subsecond dopaminergic response to METH.

Endocannabinoids shape accumbal encoding of cue-motivated behavior via CB1 receptor activation in the ventral tegmentum.

Transient increases in nucleus accumbens (NAc) dopamine concentration are observed when animals are presented with motivationally salient stimuli and are theorized to energize reward seeking. They arise from high-frequency firing of dopamine neurons in the ventral tegmental area (VTA), which also results in the release of endocannabinoids from dopamine cell bodies. In this context, endocannabinoids are thought to regulate reward seeking by modulating dopamine signaling, although a direct link has never been demonstrated. To test this, we pharmacologically manipulated endocannabinoid neurotransmission in the VTA while measuring transient changes in dopamine concentration in the NAc during reward seeking. Disrupting endocannabinoid signaling dramatically reduced, whereas augmenting levels of the endocannabinoid 2-arachidonoylglycerol (2AG) increased, cue-evoked dopamine concentrations and reward seeking. These data suggest that 2AG in the VTA regulates reward seeking by sculpting ethologically relevant patterns of dopamine release during reward-directed behavior.