Processing pathways for emotional vocalizations Abstract Emotional sounds are processed within a large cortico-subcortical network, of which the auditory cortex, the voice area, and the amygdala are the core regions. Using 7T fMRI, we have compared the effect of emotional valence (positive, neutral, and negative) and the effect of the type of environmental sounds (human vocalizations and non-vocalizations) on neural activity within individual early stage auditory areas, the voice area, and the amygdala. A two-way ANOVA was applied to the BOLD time course within each ROI. In several early stage auditory areas, it yielded a significant main effect of vocalizations and of valence, but not a significant interaction. Significant interaction as well as significant main effects of vocalization and of valence were present in the voice area; the former was driven by a significant emotional modulation of vocalizations but not of other sounds. Within the amygdala, only the main effect of valence was significant. Post-hoc correlation analysis highlighted coupling between the voice area and early stage auditory areas during the presentation of any vocalizations, and between the voice area and the right amygdala during positive vocalizations. Thus, the voice area is selectively devoted to the encoding of the emotional valence of vocalizations; it shares with several early stage auditory areas encoding characteristics for vocalizations and with the amygdala for the emotional modulation of vocalizations. These results are indicative of a dual pathway, whereby the emotional modulation of vocalizations within the voice area integrates the input from the lateral early stage auditory areas and from the amygdala.

A balanced evaluation of the evidence for adult neurogenesis in humans: implication for neuropsychiatric disorders Abstract There is a widespread belief that neurogenesis exists in adult human brain, especially in the dentate gyrus, and it is to be maintained and, if possible, augmented with different stimuli including exercise and certain drugs. Here, we examine the evidence for adult human neurogenesis and note important limitations of the methodologies used to study it. A balanced review of the literature and evaluation of the data indicate that adult neurogenesis in human brain is improbable. In fact, in several high-quality recent studies in adult human brain, unlike in adult brains of other species, neurogenesis was not detectable. These findings suggest that the human brain requires a permanent set of neurons to maintain acquired knowledge for decades, which is essential for complex high cognitive functions unique to humans. Thus, stimulation and/or injection of neural stem cells into human brains may not only disrupt brain homeostatic systems, but also disturb normal neuronal circuits. We propose that the focus of research should be the preservation of brain neurons by prevention of damage, not replacement.

Cell-type and region-specific nucleus accumbens AMPAR plasticity associated with morphine reward, reinstatement, and spontaneous withdrawal Abstract Despite evidence that morphine-related pathologies reflect adaptations in NAc glutamate signaling, substantial gaps in basic information remain. The current study examines the impact of non-contingent acute, repeated, and withdrawal-inducing morphine dosing regimens on glutamate transmission in D1- or D2-MSNs in the nucleus accumbens shell (NAcSh) and core (NAcC) sub-regions in hopes of identifying excitatory plasticity that may contribute to unique facets of opioid addiction-related behavior. Following an acute morphine injection (10 mg/kg), average miniature excitatory postsynaptic current (mEPSC) amplitude mediated by AMPA-type glutamate receptors was increased at D1-MSNs in the both the NAcShl and NAcC, whereas only the frequency of events was elevated at D2-MSNs in the NAcSh. In contrast, spontaneous somatic withdrawal induced by escalating dose of repeated morphine twice per day (20, 40, 60, 80, 100 mg/kg) enhanced mEPSC frequency specifically at D2-MSNs in the NAcSh. Similar to previous findings, excitatory drive was elevated at NAcSh D1-MSNs after 10–14 days home cage abstinence. Following abstinence, an acute drug re-exposure produced a rapid and enduring endocytosis of GluA2-containing AMPARs at D1-MSNs in the shell, that when blocked by an intra-NAc shell infusion of the Tat-GluA23Y peptide, increased reinstatement of morphine place preference—a phenomenon distinctly different than effects previously found with cocaine. The present study is the first to directly identify unique circuit specific adaptations in NAc glutamate synaptic transmission associated with morphine-related acute reward and somatic withdrawal as well as post-abstinence short-term plasticity. Moreover, while differing classes of abused drugs (i.e., psychostimulants and opioids) produce seemingly similar bidirectional plasticity in the NAc following drug re-exposure, our findings indicate this plasticity has distinct behavioral consequences.

Ensemble encoding of action speed by striatal fast-spiking interneurons Abstract Striatal fast-spiking interneurons (FSIs) potently inhibit the output neurons of the striatum and, as such, powerfully modulate action learning. Through electrical synaptic coupling, FSIs are theorized to temporally coordinate their activity. This has important implications for their ability to temporally summate inhibition on downstream striatal projection neurons. While some in vivo single-unit electrophysiological recordings of putative FSIs support coordinated firing, others do not. Moreover, it is unclear as to what aspect of action FSIs encode. To address this, we used in vivo calcium imaging of genetically identified FSIs in freely moving mice and applied machine learning analyses to decipher the relationship between FSI activity and movement. We report that FSIs exhibit ensemble activity that encodes the speed of action sub-components, including ambulation and head movements. These results suggest FSI population dynamics fit within a Hebbian model for ensemble inhibition of striatal output guiding action.

Effects of aging on sequential cognitive flexibility are associated with fronto-parietal processing deficits Abstract Albeit cognitive flexibility is well known to decline in aging, it has not been considered that this ability often requires sequential task control. That is, one may re-use tasks that have previously been abandoned in favor of another task. It is unclear whether sequential cognitive flexibility is affected in aging and what neurophysiological mechanisms and functional neuroanatomical structures are associated with these effects. We examined this question in a system neurophysiological study using EEG and source localization in healthy and elderly adults. We show that elderly people reveal deficient sequential cognitive flexibility. Elderly people encounter increased costs to overcome the inhibition of the lately abandoned task set that becomes relevant again and needs to be re-used. The neurophysiological (EEG) data show that differences in sequential cognitive flexibility between young and elderly people emerge as a consequence of two independent, dysfunctional processes: (i) the ability to suppress task-irrelevant information and (ii) the ability to re-implement a previously abandoned task set during response selection. These independent processes were associated with activation differences in inferior frontal and inferior parietal regions. The study reveals a new facet of cognitive flexibility dysfunctions in healthy elderlies.

Parsing rooms: the role of the PPA and RSC in perceiving object relations and spatial layout Abstract The perception of a scene involves grasping the global space of the scene, usually called the spatial layout, as well as the objects in the scene and the relations between them. The main brain areas involved in scene perception, the parahippocampal place area (PPA) and retrosplenial cortex (RSC), are supposed to mostly support the processing of spatial layout. Here we manipulated the objects and their relations either by arranging objects within rooms in a common way or by scattering them randomly. The rooms were then varied for spatial layout by keeping or removing the walls of the room, a typical layout manipulation. We then combined a visual search paradigm, where participants actively search for an object within the room, with multivariate pattern analysis (MVPA). Both left and right PPA were sensitive to the layout properties, but the right PPA was also sensitive to the object relations even when the information about objects and their relations is used in the cross-categorization procedure on novel stimuli. The left and right RSC were sensitive to both spatial layout and object relations, but could only use the information about object relations for cross-categorization to novel stimuli. These effects were restricted to the PPA and RSC, as other control brain areas did not display the same pattern of results. Our results underline the importance of employing paradigms that require participants to explicitly retrieve domain-specific processes and indicate that objects and their relations are processed in the scene areas to a larger extent than previously assumed.

Localization of amyloid beta peptides to locus coeruleus and medial prefrontal cortex in corticotropin releasing factor overexpressing male and female mice Abstract A culmination of evidence from the literature points to the Locus Coeruleus (LC)-Norepinephrine system as an underappreciated and understudied area of research in the context of Alzheimer’s Disease (AD). Stress is a risk factor for developing AD, and is supported by multiple clinical and preclinical studies demonstrating that amplification of the stress system disrupts cellular and molecular processes at the synapse, promoting the production and accumulation of the amyloid beta (Aβ42) peptide. Stress-induced activation of the LC is mediated by corticotropin releasing factor (CRF) and CRF receptors exhibit sex-biased stress signaling. Sex differences are evident in the neurochemical, morphological and molecular regulation of LC neurons by CRF, providing a compelling basis for the higher prevalence of stress-related disorders such as AD in females. In the present study, we examined the cellular substrates for interactions between Aβ and tyrosine hydroxylase a marker of noradrenergic somatodendritic processes in the LC, and Dopamine-β-Hydroxylase (DβH) in the infralimbic medial prefrontal cortex (ILmPFC) in mice conditionally overexpressing CRF in the forebrain (CRFOE) under a Doxycycline (DOX) regulated tetO promoter. CRFOE was sufficient to elicit a redistribution of Aβ peptides in the somatodendritic processes of the LC of male and female transgenic mice, without altering total Aβ42 protein expression levels. DOX treated groups exhibited lysosomal compartments with apparent lipofuscin and abnormal morphology, indicating potential dysfunction of these Aβ42-clearing compartments. In female DOX treated groups, swollen microvessels with lipid-laden vacuoles were also observed, a sign of blood–brain-barrier dysfunction. Finally, sex differences were observed in the prefrontal cortex, as females responded to DOX treatment with increased frequency of co-localization of Aβ42 and DβH in noradrenergic axon terminals compared to vehicle treated controls, while male groups showed no significant changes. We hypothesize that the observed sex differences in Aβ42 distribution in this model of CRF hypersignaling is based on increased responsivity of female rodent CRFR1 in the LC. Aβ42 production is enhanced during increased neuronal activation, therefore, the excitation of DOX treated female CRFOE LC neurons projecting to the mPFC may exhibit more frequent co-localization with Aβ due to increased neuronal activity of noradrenergic neurons.

Top-down control of the medial orbitofrontal cortex to nucleus accumbens core pathway in decisional impulsivity Abstract Decisional impulsivity is one of the risk factors for occurrence and development of many mental disorders, and that the dysfunctions of orbitofrontal cortex (OFC) and nucleus accumbens core (NAcC) are at least involved. Although previous studies have shown that the role of OFC as a whole in regulating decision-making impulse behavior is inconsistent, it’s still unclear that the roles of the subregions of OFC including their projections to the NAcC in decisional impulsivity. The present study was designed to investigate the roles of OFC subregions, medial OFC (mOFC) and lateral OFC (lOFC) and their projections to the NAcC in decisional impulsivity in free-moving rats. We found that rats with low level of decisional impulsivity (LI) showed higher neuronal activity in both the mOFC and lOFC, and more neurons in mOFC but not lOFC projecting to the NAcC were activated, compared with high level of decisional impulsivity (HI) rats. The mOFC-NAcC projections of LI rats showed stronger information communication in beta and low gamma oscillations in the expected reward choice and delay time windows. Further, specific activation (in HI rats) or inhibition (in LI rats) of the mOFC-NAcC pathway could partly reverse their decisional impulsive behaviors. The findings first demonstrated that the mOFC-NAcC pathway was more important than the lOFC-NAcC pathway to the top-down control in decisional impulsivity, which could be a new neural physiological mechanism for psychiatric disorders associated with decisional impulsivity.

Stability of neuronal avalanches and long-range temporal correlations during the first year of life in human infant Abstract During infancy, the human brain rapidly expands in size and complexity as neural networks mature and new information is incorporated at an accelerating pace. Recently, it was shown that single electrode EEG in preterms at birth exhibits scale-invariant intermittent bursts. Yet, it is currently not known whether the normal infant brain, in particular, the cortex maintains a distinct dynamical state during development that is characterized by scale-invariant spatial as well as temporal aspects. Here we employ dense-array EEG recordings acquired from the same infants at 6 and 12 months of age to characterize brain activity during an auditory oddball task. We show that suprathreshold events organize as spatiotemporal clusters whose size and duration are power-law distributed, the hallmark of neuronal avalanches. Time series of local suprathreshold EEG events display significant long-range temporal correlations (LRTCs). No differences were found between 6 and 12 months, demonstrating stability of avalanche dynamics and LRTCs during the first year after birth. These findings demonstrate that the infant brain is characterized by distinct spatiotemporal dynamical aspects that are in line with expectations of a critical cortical state. We suggest that critical state dynamics, which theory and experiments have shown to be beneficial for numerous aspects of information processing, are maintained by the infant brain to process an increasingly complex environment during development.

Role of the supplementary motor area in auditory sensory attenuation Abstract Self-generated tones elicit smaller brain responses as compared to externally generated tones. This phenomenon known as sensory attenuation has been explained in terms of an internal forward model in which the brain predicts the upcoming events and thereby attenuates the sensory processing. Such prediction processes have been suggested to occur via an efference copy of the motor command that is sent from the motor system to the lower order sensory cortex. However, little is known about how the prediction is implemented in the brain’s network organization. Because the supplementary motor area (SMA) is a primary brain structure of the motor system, we attributed the implementation of the prediction to the SMA. To address this question, we examined generative network models for auditory ERPs. ERPs were evoked by either a self-generated or externally generated tone, while subjects were paying attention to their motor action or to the tone. The tone itself was the same throughout all conditions. The network models consisted of three subsets embedding alternative hypotheses of the hierarchical structures: (1) auditory fields of the temporal lobe, (2) adding connections to the SMA, and (3) adding prediction signal to the SMA. The model comparison revealed that all ERP responses were mediated by the network connections across the auditory cortex and the SMA. Importantly, the prediction signal to the SMA was required when the tone was self-generated irrespective of the attention factor, whereas the externally generated tone did not require the prediction. We discussed these results in the context of the predictive coding framework.