Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disease mainly characterized by motor incoordination because of progressive cerebellar degeneration. SCA7 is caused by polyglutamine expansion in ATXN7, a subunit of the transcriptional coactivator SAGA, which harbors histone modification activities. Polyglutamine expansions in specific proteins are also responsible for SCA1-SCA3, SCA6, and SCA17; however, the converging and diverging pathomechanisms remain poorly understood. Using a new SCA7 knock-in mouse, SCA7140Q/5Q, we analyzed gene expression in the cerebellum and assigned gene deregulation to specific cell types using published datasets. Gene deregulation affects all cerebellar cell types, although at variable degree, and correlates with alterations of SAGA-dependent epigenetic marks. Purkinje cells (PCs) are by far the most affected neurons and show reduced expression of 83 cell-type identity genes, including these critical for their spontaneous firing activity and synaptic func...

The postrhinal area (POR) is a known center for integrating spatial with nonspatial visual information and a possible hub for influencing landmark navigation by affective input from the amygdala. This may involve specific circuits within muscarinic acetylcholine receptor 2 (M2)-positive (M2+) or M2– modules of POR that associate inputs from the thalamus, cortex, and amygdala, and send outputs to the entorhinal cortex. Using anterograde and retrograde labeling with conventional and viral tracers in male and female mice, we found that all higher visual areas of the ventral cortical stream project to the amygdala, while such inputs are absent from primary visual cortex and dorsal stream areas. Unexpectedly for the presumed salt-and-pepper organization of mouse extrastriate cortex, tracing results show that inputs from the dorsal lateral geniculate nucleus and lateral posterior nucleus were spatially clustered in layer 1 (L1) and overlapped with M2+ patches of POR. In contrast, input from the amygdala to L1 of...

Different species of animals can discriminate numerosity, the countable number of objects in a set. The representations of countable numerosities have been deciphered down to the level of single neurons. However, despite its importance for human number theory, a special numerical quantity, the empty set (numerosity zero), has remained largely unexplored. We explored the behavioral and neuronal representation of the empty set in carrion crows. Crows were trained to discriminate small numerosities including the empty set. Performance data showed a numerical distance effect for the empty set in one crow, suggesting that the empty set and countable numerosities are represented along the crows' “mental number line.” Single-cell recordings in the endbrain region nidopallium caudolaterale (NCL) showed a considerable proportion of NCL neurons tuned to the preferred numerosity zero. As evidenced by neuronal distance and size effects, NCL neurons integrated the empty set in the neural number line. A subsequent neuro...

Useful memory must balance between stability and malleability. This puts effective memory storage at odds with plasticity processes, such as reconsolidation. What becomes of memory maintenance processes during synaptic plasticity is unknown. Here we examined the fate of the memory maintenance protein PKMζ during memory destabilization and reconsolidation in male rats. We found that NMDAR activation and proteasome activity induced a transient reduction in PKMζ protein following retrieval. During reconsolidation, new PKMζ was synthesized to re-store the memory. Failure to synthesize new PKMζ during reconsolidation impaired memory but uninterrupted PKMζ translation was not necessary for maintenance itself. Finally, NMDAR activation was necessary to render memories vulnerable to the amnesic effect of PKMζ-antisense. These findings outline a transient disruption and renewal of the PKMζ memory maintenance mechanism during plasticity. We argue that dynamic changes in PKMζ protein levels can serve as an exemplary ...

Repeated cocaine exposure causes dendritic spine loss in the orbitofrontal cortex, which might contribute to poor orbitofrontal cortical function following drug exposure. One challenge, however, has been verifying links between neuronal structural plasticity and behavior, if any. Here we report that cocaine self-administration triggers the loss of dendritic spines on excitatory neurons in the orbitofrontal cortex of male and female mice (as has been reported in rats). To understand functional consequences, we locally ablated neuronal β1-integrins, cell adhesion receptors that adhere cells to the extracellular matrix and thus support dendritic spine stability. Degradation of β1-integrin tone: 1) caused dendritic spine loss; 2) exaggerated cocaine-seeking responses in a cue-induced reinstatement test; and 3) impaired the ability of mice to integrate new learning into familiar routines – a key function of the orbitofrontal cortex. Stimulating Abl-related gene (Arg) kinase, over-expressing Proline-rich tyrosin...

The orbitofrontal cortex (OFC) is a brain region involved in higher-order decision-making. Rodent studies show that cocaine self-administration (CSA) reduces OFC contribution to goal-directed behavior and behavioral strategies to avoid drug intake. This change in OFC function persists for many weeks after cocaine withdrawal, suggesting involvement in the process of addiction. The mechanisms underlying impaired OFC function by cocaine are not well-understood. However, studies implicate altered OFC serotonin (5-HT) function in disrupted cognitive processes during addiction and other psychiatric disorders. Thus, it is hypothesized that cocaine impairment of OFC function involves changes in 5-HT signaling, and previous work shows that 5-HT1A and 5-HT2A receptor-mediated effects on OFC pyramidal neurons (PyNs) are impaired weeks after cocaine withdrawal. However, 5-HT effects on other contributors to OFC circuit function have not been fully investigated, including the parvalbumin-containing, fast-spiking intern...

Oscillation-based models of speech perception postulate a cortical computational principle by which decoding is performed within a window structure derived by a segmentation process. Segmentation of syllable-size chunks is realized by a theta oscillator. We provide evidence for an analogous role of a delta oscillator in the segmentation of phrase-sized chunks. We recorded Magnetoencephalography (MEG) in humans, while participants performed a target identification task. Random-digit strings, with phrase-long chunks of two digits, were presented at chunk rates of 1.8 Hz or 2.6 Hz, inside or outside the delta frequency band (defined here to be 0.5 - 2 Hz). Strong periodicities were elicited by chunk rates inside of delta in superior, middle temporal areas and speech-motor integration areas. Periodicities were diminished or absent for chunk rates outside delta, in line with behavioral performance. Our findings show that prosodic chunking of phrase-sized acoustic segments is correlated with acoustic-driven delt...

Identifying true motivation for Pareto lies, which are mutually beneficial for both the liar and others, can be challenging because different covert motivations can lead to identical overt behavior. In this study, we adopted a brain-fingerprinting approach, combining both univariate and multivariate analyses to estimate individual measures of selfish motivation in Pareto lies by the degree of multivoxel neural representation in the medial prefrontal cortex (MPFC) for Pareto lies conforms with those for selfish vs. altruistic lies in human participants of either sex. An increase in selfish motivation for Pareto lies was associated with higher mean-level activity in both ventral and rostral MPFC. The former showed an increased pattern similarity to selfish lies and the latter showed a decreased pattern similarity to altruistic lies. Higher ventral MPFC pattern similarity predicted faster response time in Pareto lies. Our findings demonstrated that hidden selfish motivation in white lies can be revealed by ne...

Synapses are actively dismantled to mediate circuit refinement, but the developmental pathways that regulate synaptic disassembly are largely unknown. We have previously shown that the epithelial sodium channel ENaC/UNC-8 triggers an activity-dependent mechanism that drives the removal of presynaptic proteins liprin-α/SYD-2, Synaptobrevin/SNB-1, RAB-3 and Endophilin/UNC-57 in remodeling GABAergic neurons in C. elegans (Miller-Fleming et al., 2016). Here, we report that the conserved transcription factor Iroquois/IRX-1 regulates UNC-8 expression as well as an additional pathway, independent of UNC-8, that functions in parallel to dismantle functional presynaptic terminals. We show that the additional IRX-1-regulated pathway is selectively required for the removal of the presynaptic proteins, Munc13/UNC-13 and ELKS, which normally mediate synaptic vesicle fusion and neurotransmitter release. Our findings are notable because they highlight the key role of transcriptional regulation in synapse elimination duri...