Neocortical and cerebellar malformations affect flurothyl-induced seizures in female C57BL/6J mice.

Brain malformations cause cognitive disability and seizures in both human and animal models. Highly laminated structures such as the neocortex and cerebellum are vulnerable to malformation, affecting lamination and neuronal connectivity as well as causing heterotopia. The objective of the present study was to determine if sporadic neocortical and/or cerebellar malformations in C57BL/6J mice are correlated with reduced seizure threshold. The inhaled chemi-convulsant flurothyl was used to induce generalized, tonic-clonic seizures in male and female C57BL/6J mice, and the time to seizure onset was recorded as a functional correlate of brain excitability changes. Following seizures, mice were euthanized, and brains were extracted for histology. Cryosections of the neocortex and cerebellar vermis were stained and examined for the presence of molecular layer heterotopia as previously described in C57BL/6J mice. Over 60% of mice had neocortical and/or cerebellar heterotopia. No sex differences were observed in the prevalence of malformations. Significantly reduced seizure onset time was observed dependent on sex and the type of malformation present. These results raise important questions regarding the presence of malformations in C57BL/6J mice used in the study of brain development, epilepsy, and many other diseases of the nervous system.

Haploinsufficiency of Shank3 in Mice Selectively Impairs Target Odor Recognition in Novel Background Odors.

Individuals with mutations in a single copy of the SHANK3 gene present with social interaction deficits. Although social behavior in mice depends on olfaction, mice with mutations in a single copy of the Shank3 gene do not have olfactory deficits in simple odor identification tasks (Drapeau et al., 2018). Here, we tested olfaction in mice with mutations in a single copy of the Shank3 gene (Peça et al., 2011) using a complex odor task and imaging in awake mice. Average glomerular responses in the olfactory bulb of Shank3B +/- were correlated with WT mice. However, there was increased trial-to-trial variability in the odor responses for Shank3B +/- mice. Simulations demonstrated that this increased variability could affect odor detection in novel environments. To test whether performance was affected by the increased variability, we tested target odor recognition in the presence of novel background odors using a recently developed task (Li et al., 2023). Head-fixed mice were trained to detect target odors in the presence of known background odors. Performance was tested using catch trials where the known background odors were replaced by novel background odors. We compared the performance of eight Shank3B +/- mice (five males, three females) on this task with six WT mice (three males, three females). Performance for known background odors and learning rates were similar between Shank3B +/- and WT mice. However, when tested with novel background odors, the performance of Shank3B +/- mice dropped to almost chance levels. Thus, haploinsufficiency of the Shank3 gene causes a specific deficit in odor detection in novel environments. Our results are discussed in the context of other Shank3 mouse models and have implications for understanding olfactory function in neurodevelopmental disorders.SIGNIFICANCE STATEMENT People and mice with mutations in a single copy in the synaptic gene Shank3 show features seen in autism spectrum disorders, including social interaction deficits. Although mice social behavior uses olfaction, mice with mutations in a single copy of Shank3 have so far not shown olfactory deficits when tested using simple tasks. Here, we used a recently developed task to show that these mice could identify odors in the presence of known background odors as well as wild-type mice. However, their performance fell below that of wild-type mice when challenged with novel background odors. This deficit was also previously reported in the Cntnap2 mouse model of autism, suggesting that odor detection in novel backgrounds is a general deficit across mouse models of autism.

Robust odor identification in novel olfactory environments in mice.

Relevant odors signaling food, mates, or predators can be masked by unpredictable mixtures of less relevant background odors. Here, we developed a mouse behavioral paradigm to test the role played by the novelty of the background odors. During the task, mice identified target odors in previously learned background odors and were challenged by catch trials with novel background odors, a task similar to visual CAPTCHA. Female wild-type (WT) mice could accurately identify known targets in novel background odors. WT mice performance was higher than linear classifiers and the nearest neighbor classifier trained using olfactory bulb glomerular activation patterns. Performance was more consistent with an odor deconvolution method. We also used our task to investigate the performance of female Cntnap2-/- mice, which show some autism-like behaviors. Cntnap2-/- mice had glomerular activation patterns similar to WT mice and matched WT mice target detection for known background odors. However, Cntnap2-/- mice performance fell almost to chance levels in the presence of novel backgrounds. Our findings suggest that mice use a robust algorithm for detecting odors in novel environments and this computation is impaired in Cntnap2-/- mice.

Neurodevelopmental malformations of the cerebellum and neocortex in the Shank3 and Cntnap2 mouse models of autism.

There are many mouse models of autism with broad use in neuroscience research. Genetic background can be a major contributor to the phenotype observed in any mouse model of disease, including genetic models of autism. C57BL/6 mice display spontaneous glio-neuronal heterotopia in the cerebellar vermis and neocortex which may also exist in mouse models of autism created on this background. In the present report, we document the presence of cerebellar and neocortical heterotopia in heterozygous and KO Shank3 and Cntnap2 mice which are due to the C57BL/6 genotype and discuss the role these malformations may play in research using these genetic models of autism.

Cortical Feedback Decorrelates Olfactory Bulb Output in Awake Mice.

The olfactory bulb receives rich glutamatergic projections from the piriform cortex. However, the dynamics and importance of these feedback signals remain unknown. Here, we use multiphoton calcium imaging to monitor cortical feedback in the olfactory bulb of awake mice and further probe its impact on the bulb output. Responses of feedback boutons were sparse, odor specific, and often outlasted stimuli by several seconds. Odor presentation either enhanced or suppressed the activity of boutons. However, any given bouton responded with stereotypic polarity across multiple odors, preferring either enhancement or suppression. Feedback representations were locally diverse and differed in dynamics across bulb layers. Inactivation of piriform cortex increased odor responsiveness and pairwise similarity of mitral cells but had little impact on tufted cells. We propose that cortical feedback differentially impacts these two output channels of the bulb by specifically decorrelating mitral cell responses to enable odor separation.

A corticothalamic circuit model for sound identification in complex scenes.

The identification of the sound sources present in the environment is essential for the survival of many animals. However, these sounds are not presented in isolation, as natural scenes consist of a superposition of sounds originating from multiple sources. The identification of a source under these circumstances is a complex computational problem that is readily solved by most animals. We present a model of the thalamocortical circuit that performs level-invariant recognition of auditory objects in complex auditory scenes. The circuit identifies the objects present from a large dictionary of possible elements and operates reliably for real sound signals with multiple concurrently active sources. The key model assumption is that the activities of some cortical neurons encode the difference between the observed signal and an internal estimate. Reanalysis of awake auditory cortex recordings revealed neurons with patterns of activity corresponding to such an error signal.

Engaging in an auditory task suppresses responses in auditory cortex.

Although systems that are involved in attentional selection have been studied extensively, much less is known about nonselective systems. To study these preparatory mechanisms, we compared activity in auditory cortex that was elicited by sounds while rats performed an auditory task ('engaged') with activity that was elicited by identical stimuli while subjects were awake but not performing a task ('passive'). We found that engagement suppressed responses, an effect that was opposite in sign to that elicited by selective attention. In the auditory thalamus, however, engagement enhanced spontaneous firing rates but did not affect evoked responses. These results indicate that neural activity in auditory cortex cannot be viewed simply as a limited resource that is allocated in greater measure as the state of the animal passes from somnolent to passively listening to engaged and attentive. Instead, the engaged condition possesses a characteristic and distinct neural signature in which sound-evoked responses are paradoxically suppressed.

Millisecond-scale differences in neural activity in auditory cortex can drive decisions.

Neurons in the auditory cortex can lock to the fine timing of acoustic stimuli with millisecond precision, but it is not known whether this precise spike timing can be used to guide decisions. We used chronically implanted microelectrode pairs to stimulate neurons in the rat auditory cortex directly and found that rats can exploit differences in the timing of cortical activity that are as short as 3 ms to guide decisions.