Cell-type-specific hypothalamic pathways to brainstem drive context-dependent strategies in response to stressors.

Adaptive behavioral responses to stressors are critical for survival. However, which brain areas orchestrate switching the appropriate stress responses to distinct contexts is an open question. This study aimed to identify the cell-type-specific brain circuitry governing the selection of distinct behavioral strategies in response to stressors. Through novel mouse behavior paradigms, we observed distinct stressor-evoked behaviors in two psycho-spatially distinct contexts characterized by stressors inside or outside the safe zone. The identification of brain regions activated in both conditions revealed the involvement of the dorsomedial hypothalamus (DMH). Further investigation using optogenetics, chemogenetics, and photometry revealed that glutamatergic projections from the DMH to periaqueductal gray (PAG) mediated responses to inside stressors, while GABAergic projections, particularly from tachykinin1-expressing neurons, played a crucial role in coping with outside stressors. These findings elucidate the role of cell-type-specific circuitry from the DMH to the PAG in shaping behavioral strategies in response to stressors. These findings have the potential to advance our understanding of fundamental neurobiological processes and inform the development of novel approaches for managing context-dependent and anxiety-associated pathological conditions such as agoraphobia and claustrophobia.

Thalamic regulation of ocular dominance plasticity in adult visual cortex.

Experience-dependent plasticity in the adult visual system is generally thought of as a cortical process. However, several recent studies have shown that perceptual learning or monocular deprivation can also induce plasticity in the adult dorsolateral geniculate nucleus (dLGN) of the thalamus. How plasticity in the thalamus and cortex interact in the adult visual system is ill-understood. To assess the influence of thalamic plasticity on plasticity in primary visual cortex (V1), we made use of our previous finding that during the critical period ocular dominance (OD) plasticity occurs in dLGN and requires thalamic synaptic inhibition. Using multielectrode recordings we find that this is also true in adult mice, and that in the absence of thalamic inhibition and plasticity, OD plasticity in adult V1 is absent. To study the influence of V1 on thalamic plasticity, we silenced V1 and show that during the critical period, but not in adulthood, the OD shift in dLGN is partially caused by feedback from V1. We conclude that during adulthood the thalamus plays an unexpectedly dominant role in experience-dependent plasticity in V1. Our findings highlight the importance of considering the thalamus as a potential source of plasticity in learning events that are typically thought of as cortical processes.

The zona incerta in control of novelty seeking and investigation across species.

Many organisms rely on a capacity to rapidly replicate, disperse, and evolve when faced with uncertainty and novelty. But mammals do not evolve and replicate quickly. They rely on a sophisticated nervous system to generate predictions and select responses when confronted with these challenges. An important component of their behavioral repertoire is the adaptive context-dependent seeking or avoiding of perceptually novel objects, even when their values have not yet been learned. Here, we outline recent cross-species breakthroughs that shed light on how the zona incerta (ZI), a relatively evolutionarily conserved brain area, supports novelty-seeking and novelty-related investigations. We then conjecture how the architecture of the ZI's anatomical connectivity - the wide-ranging top-down cortical inputs to the ZI, and its specifically strong outputs to both the brainstem action controllers and to brain areas involved in action value learning - place the ZI in a unique role at the intersection of cognitive control and learning.

A cell type-specific cortico-subcortical brain circuit for investigatory and novelty-seeking behavior.

Exploring the physical and social environment is essential for understanding the surrounding world. We do not know how novelty-seeking motivation initiates the complex sequence of actions that make up investigatory behavior. We found in mice that inhibitory neurons in the medial zona incerta (ZIm), a subthalamic brain region, are essential for the decision to investigate an object or a conspecific. These neurons receive excitatory input from the prelimbic cortex to signal the initiation of exploration. This signal is modulated in the ZIm by the level of investigatory motivation. Increased activity in the ZIm instigates deep investigative action by inhibiting the periaqueductal gray region. A subpopulation of inhibitory ZIm neurons expressing tachykinin 1 (TAC1) modulates the investigatory behavior.

Contrast-Dependence of Temporal Frequency Tuning in Mouse V1.

The perception of speed is influenced by visual contrast. In primary visual cortex (V1), an early stage in the visual perception pathway, the neural tuning to speed is directly related to the neural tuning to temporal frequency of stimulus changes. The influence of contrast on speed perception can be caused by the joint dependency of neural responses in V1 on temporal frequency and contrast. Here, we investigated how tuning to contrast and temporal frequency in V1 of anesthetized mice are related. We found that temporal frequency tuning is contrast-dependent. V1 was more responsive at lower temporal frequencies than the dLGN, consistent with previous work at high contrast. The temporal frequency tuning moves toward higher temporal frequencies with increasing contrast. The low half-maximum temporal frequency does not change with contrast. The Heeger divisive normalization equation provides a good fit to many response characteristics in V1, but does not fit the dependency of temporal frequency and contrast with set of parameters for all temporal frequencies. Different mechanisms for normalization in the visual cortex may predict different relationships between temporal frequency and contrast non-linearity. Our data could help to make a model selection.

Long-term enhancement of visual responses by repeated transcranial electrical stimulation of the mouse visual cortex.

BACKGROUND: Transcranial electrical stimulation (tES) is a popular method to modulate brain activity by sending a weak electric current through the head. Despite its popularity, long-term effects are poorly understood. OBJECTIVE: We wanted to test if anodal tES immediately changes cerebral responses to visual stimuli, and if repeated sessions of tES produce plasticity in these responses. METHODS: We applied repeated anodal tES, like transcranial direct current stimulation (tDCS), but pulsed (8 s on, 10 s off), to the visual cortex of mice while visually presenting gratings. We measured the responses to these visual stimuli in the visual cortex using the genetically encoded calcium indicator GCaMP3. RESULTS: We found an increase in the visual response when concurrently applying tES on the bone without skin (epicranially). This increase was only transient when tES was applied through the skin (transcutaneous). There was no immediate after-effect of tES. However, repeated transcutaneous tES for four sessions at two-day intervals increased the visual response in the visual cortex. This increase was not specific to the grating stimulus coupled to tES and also occurred for an orthogonal grating presented in the same sessions but without concurrent tES. No increase was found in mice that received no tES. CONCLUSION: Our study provides evidence that tES induces long-term changes in the mouse brain. Results in mice do not directly translate to humans, because of differences in stimulation protocols and the way current translates to electric field strength in vastly different heads.

Functional modulation of primary visual cortex by the superior colliculus in the mouse.

The largest targets of retinal input in mammals are the dorsal lateral geniculate nucleus (dLGN), a relay to the primary visual cortex (V1), and the superior colliculus. V1 innervates and influences the superior colliculus. Here, we find that, in turn, superior colliculus modulates responses in mouse V1. Optogenetically inhibiting the superior colliculus reduces responses in V1 to optimally sized stimuli. Superior colliculus could influence V1 via its strong projection to the lateral posterior nucleus (LP/Pulvinar) or its weaker projection to the dLGN. Inhibiting superior colliculus strongly reduces activity in LP. Pharmacologically silencing LP itself, however, does not remove collicular modulation of V1. The modulation is instead due to a collicular gain modulation of the dLGN. Surround suppression operating in V1 explains the different effects for differently sized stimuli. Computations of visual saliency in the superior colliculus can thus influence tuning in the visual cortex via a tectogeniculate pathway.

Visual Processing by Calretinin Expressing Inhibitory Neurons in Mouse Primary Visual Cortex.

Inhibition in the cerebral cortex is delivered by a variety of GABAergic interneurons. These cells have been categorized by their morphology, physiology, gene expression and connectivity. Many of these classes appear to be conserved across species, suggesting that the classes play specific functional roles in cortical processing. What these functions are, is still largely unknown. The largest group of interneurons in the upper layers of mouse primary visual cortex (V1) is formed by cells expressing the calcium-binding protein calretinin (CR). This heterogeneous class contains subsets of vasoactive intestinal polypeptide (VIP) interneurons and somatostatin (SOM) interneurons. Here we show, using in vivo two-photon calcium imaging in mice, that CR neurons can be sensitive to stimulus orientation, but that they are less selective on average than the overall neuronal population. Responses of CR neurons are suppressed by a surrounding stimulus, but less so than the overall population. In rats and primates, CR interneurons have been suggested to provide disinhibition, but we found that in mice their in vivo activation by optogenetics causes a net inhibition of cortical activity. Our results show that the average functional properties of CR interneurons are distinct from the averages of the parvalbumin, SOM and VIP interneuron populations.

Thalamic inhibition regulates critical-period plasticity in visual cortex and thalamus.

During critical periods of development, experience shapes cortical circuits, resulting in the acquisition of functions used throughout life. The classic example of critical-period plasticity is ocular dominance (OD) plasticity, which optimizes binocular vision but can reduce the responsiveness of the primary visual cortex (V1) to an eye providing low-grade visual input. The onset of the critical period of OD plasticity involves the maturation of inhibitory synapses within V1, specifically those containing the GABAA receptor α1 subunit. Here we show that thalamic relay neurons in mouse dorsolateral geniculate nucleus (dLGN) also undergo OD plasticity. This process depends on thalamic α1-containing synapses and is required for consolidation of the OD shift in V1 during long-term deprivation. Our findings demonstrate that thalamic inhibitory circuits play a central role in the regulation of the critical period. This has far-reaching consequences for the interpretation of studies investigating the molecular and cellular mechanisms regulating critical periods of brain development.

Visual Cortex Limits Pop-Out in the Superior Colliculus of Awake Mice.

We detect objects more readily if they differ from their surroundings in motion, color, or texture. This increased saliency is thought to be related to increased responses in the visual cortex. The superior colliculus is another brain area involved in vision and especially in directing gaze and attention. In this study, we show that differences in texture orientation also increase responses in the superficial layers of the superior colliculus that receive retinal and cortical input. We found that gratings evoke more neural response when surrounded by orthogonal gratings than when surrounded by parallel gratings, particularly in the awake mouse. This pop-out is not originating from the visual cortex, and silencing visual cortex increased the relative difference in response. A model shows that this can result from retinotopically matched excitation from visual cortex to the superior colliculus. We suggest that the perceptual saliency of a stimulus differing from its surround in a low-level feature like grating orientation could depend on visual processing in the superior colliculus.

Complexity of weighted graph: A new technique to investigate structural complexity of brain activities with applications to aging and autism.

In recent years complexity of the brain structure in healthy and disordered subjects has been studied increasingly. But to the best of the authors' knowledge, researchers so far have investigated the structural complexity only in the context of two restricted networks known as Small-World and Scale-free networks; whereas other aspects of the structural complexity of brain activities may be affected by aging and neurodegenerative disorders such as the Alzheimer's disease and autism spectrum disorder. In this study, two general complexity metrics of graphs, Graph Index Complexity and Offdiagonal Complexity are proposed as general measures of complexity, not restricted to SWN only. They are adopted to measure the structural complexity of the weighted graphs instead of the common binary graphs. Fuzzy Synchronization Likelihood is applied to the EEGs and their sub-bands, as a functional connectivity metric of the brain, to construct the functional connectivity graphs. Two applications are used to evaluate the efficacy of the complexity measures: diagnosis of autism and aging, both based on EEG. It was discovered that the Graph Index Complexity of gamma band is discriminative in distinguishing autistic children from non-autistic children. Also, Offdiagonal Complexity of theta band in young subjects was observed to be significantly different than old subjects. This study shows that changes in the structure of functional connectivity of brain in disorders and different healthy states can be revealed by unrestricted metrics of graph complexity. While the applications presented in this paper are based on EEG, the approach is general and can be used with other modalities such as fMRI, MEG, etc. Further, it can be used to study every other neurological and psychiatric disorder.

Preference for concentric orientations in the mouse superior colliculus.

The superior colliculus is a layered structure important for body- and gaze-orienting responses. Its superficial layer is, next to the lateral geniculate nucleus, the second major target of retinal ganglion axons and is retinotopically organized. Here we show that in the mouse there is also a precise organization of orientation preference. In columns perpendicular to the tectal surface, neurons respond to the same visual location and prefer gratings of the same orientation. Calcium imaging and extracellular recording revealed that the preferred grating varies with retinotopic location, and is oriented parallel to the concentric circle around the centre of vision through the receptive field. This implies that not all orientations are equally represented across the visual field. This makes the superior colliculus different from visual cortex and unsuitable for translation-invariant object recognition and suggests that visual stimuli might have different behavioural consequences depending on their retinotopic location.

Complexity of functional connectivity networks in mild cognitive impairment subjects during a working memory task.

OBJECTIVES: The objective is to study the changes of brain activity in patients with mild cognitive impairment (MCI). Using magneto-encephalogram (MEG) signals, the authors investigate differences of complexity of functional connectivity network between MCI and normal elderly subjects during a working memory task. METHODS: MEGs are obtained from 18 right handed patients with MCI and 19 age-matched elderly participants without cognitive impairment used as the control group. The brain networks' complexities are measured by Graph Index Complexity (C(r)) and Efficiency Complexity (C(e)). RESULTS: The results obtained by both measurements show complexity of functional networks involved in the working memory function in MCI subjects is reduced at alpha and theta bands compared with subjects with control subjects, and at the theta band this reduction is more pronounced in the whole brain and intra left hemisphere. CONCLUSIONS: C(e) would be a better measurement for showing the global differences between normal and MCI brains compared with C(r). SIGNIFICANCE: The high accuracy of the classification shows C(e) at theta band can be used as an index for assessing deficits associated with working memory, a good biomarker for diagnosis of MCI.

Disrupted small-world brain network in children with Down Syndrome.

OBJECTIVE: To explore how the global organization or topology of the functional brain connectivity (FBC) is affected in Down Syndrome (DS). METHODS: As the brain is a highly complex network including numerous nonlinearly interacted neuronal areas, the FBCs of typically developing (TD) children and DS patients were computed using a nonlinear synchronization method. Then the differences in global organization of the obtained FBCs of the two groups were analyzed, in all electroencephalogram (EEG) frequency bands, in the framework of Small-Worldness Network (a network with optimum balance between segregation and integration of information). RESULTS: The topology of the functional connectivity of DS patients is disrupted in the whole brain in alpha and theta bands, and especially in the left intra-hemispheric brain networks in upper alpha band. CONCLUSIONS: The global organization of the DS brain does not resemble a Small-World network, but it works as a random network. SIGNIFICANCE: It is the first study on global organization of the FBC in DS.

Spatiotemporal analysis of relative convergence of EEGs reveals differences between brain dynamics of depressive women and men.

A new nonlinear technique for analysis of brain dynamics called spatiotemporal analysis of relative convergence (STARC) of electroencephalograms (EEGs) is introduced, based on the relative convergence of EEGs of different loci. This technique shows how many times EEGs of each loci pair converge together, which in turn is used as an indicator to determine the different neuronal regions involved in performing the same task. A higher STARC value indicates that more regions are recruited to perform the same task. The STARC methodology was used to reveal sex difference pathophysiology and brain dynamics, using EEG data from 11 male and 11 female adults with major depressive disorder (MDD). The results show significant differences in relative convergences of EEGs of intraleft temporal and frontoleft temporal lobes at δ band, between male and female patients.

Linear and nonlinear analysis of brain dynamics in children with cerebral palsy.

This study was carried out to determine linear and nonlinear changes of brain dynamics and their relationships with the motor dysfunctions in CP children. For this purpose power of EEG frequency bands (as a linear analysis) and EEG fractality (as a nonlinear analysis) were computed in eyes-closed resting state and statistically compared between 26 CP and 26 normal children. Based on these characteristics accuracy of the classification between the two groups was obtained by enhanced probabilistic neural network (EPNN). Severity of gross motor and manual disabilities was determined by standard systems and the relation between the deficient brain dynamics and severity of the motor dysfunctions was obtained by Pearson's correlation coefficient. A definitely higher delta and lower theta and alpha powers, and higher EEG complexity in CP patients. As such a high accuracy of 94.8% in distinguishing the two groups was obtained. Moreover significant positive correlations were found between beta power and severity of manual disabilities and gross motor dysfunctions in the boys with CP. It is concluded that the obtained brain dynamics' characteristics are useful in diagnosis of CP. Furthermore severity of the motor dysfunctions in boys with CP could be evaluated by the beta activity.

Brain activity of women is more fractal than men.

Investigating gender differences of the brain is of both scientific and clinical importance, as understanding such differences may be helpful for improving gender specific treatments of neuropsychiatric disorders. As brain is a highly complex system, it is crucial to investigate its activity in terms of nonlinear dynamics. However, there are few studies that investigated gender differences based on dynamical characteristics of the brain. Fractal dimension (FD) is a key characteristic of the brain dynamics which indicates the level of complexity on which the neuronal regions function or interact and quantifies the associated brain processes on a scale ranging from fully deterministic to fully random. This study investigates the gender differences of brain dynamics, comparing fractal dimension of scalp EEGs (in eyes-closed resting state) of 34 female and 34 male healthy adults. The results showed significantly greater FDs in females compared to males in all brain regions except in lateral and occipital lobes. This indicates a higher complexity of the brain dynamics in females relative to males. The high accuracies of 87.8% and 93.1% obtained by logistic regression and enhanced probabilistic neural network, respectively, in discriminating between the gender groups based on the FDs also confirmed the great gender differences of complexity of brain activities. The results showed that delta, alpha, and beta bands are the frequency bands that contribute most to the gender differences in brain complexity. Furthermore, the lateralization analysis showed the leftward lateralization of complexity in females is greater than in males.

Global organization of functional brain connectivity in methamphetamine abusers.

OBJECTIVE: This study aimed to determine effects of chronic methamphetamine (MA) abuse on global organization of the functional brain connectivity. METHODS: Eyes-closed resting-state EEGs of 36 MA abusers and 36 age-matched healthy subjects were recorded using a 32-channel system. The EEGs (1-60 Hz), after removing artifacts, were decomposed into the conventional EEG bands. Using visibility graph similarity (VGS) and coherence methods, the VGS and coherence matrices in each EEG band were constructed. Then the Small-World Network properties, clustering coefficient (C), mean path length (L) and C/L, of the VGS and coherence matrices, were computed in all EEG bands. Then using the Mann-Whitney test and an artificial neural network the differences of C, L and C/L between the two groups were evaluated. RESULTS: The MA abusers showed higher C, lower L and higher C/L at the gamma band (p-value < 0.005). An accuracy of 82.8% in discriminating the two groups was obtained by the classifier. CONCLUSIONS: The topology of the functional brain connectivity is disrupted in MA abusers, as depicted by deviation from Small-Worldness in the gamma band. SIGNIFICANCE: This is the first but quasi-experimental study showing disrupted topology of the functional brain networks in MA abusers.

Down syndrome's brain dynamics: analysis of fractality in resting state.

To the best knowledge of the authors there is no study on nonlinear brain dynamics of down syndrome (DS) patients, whereas brain is a highly complex and nonlinear system. In this study, fractal dimension of EEG, as a key characteristic of brain dynamics, showing irregularity and complexity of brain dynamics, was used for evaluation of the dynamical changes in the DS brain. The results showed higher fractality of the DS brain in almost all regions compared to the normal brain, which indicates less centrality and higher irregular or random functioning of the DS brain regions. Also, laterality analysis of the frontal lobe showed that the normal brain had a right frontal laterality of complexity whereas the DS brain had an inverse pattern (left frontal laterality). Furthermore, the high accuracy of 95.8 % obtained by enhanced probabilistic neural network classifier showed the potential of nonlinear dynamic analysis of the brain for diagnosis of DS patients. Moreover, the results showed that the higher EEG fractality in DS is associated with the higher fractality in the low frequencies (delta and theta), in broad regions of the brain, and the high frequencies (beta and gamma), majorly in the frontal regions.

Fuzzy Synchronization Likelihood-wavelet methodology for diagnosis of autism spectrum disorder.

This paper presents a methodology for investigation of functional connectivity in patients with autism spectrum disorder (ASD) using Fuzzy Synchronization Likelihood (Fuzzy SL). Fuzzy SLs between and within brain regions are calculated in all EEG sub-bands produced by the wavelet decomposition as well as in the full-band EEG. Then, discriminative Fuzzy SLs between and within different regions and different EEG sub-bands or full-band EEG for distinguishing autistic children from healthy control children are determined based on Analysis of Variation (ANOVA). Finally, the selected features are used as input to an Enhanced Probabilistic Neural Network classifier to make an accurate diagnosis of ASD based on the detected differences in the regional functional connectivity of autistic and healthy EEGs. The methodology is validated using EEG data obtained from 9 autistic and 9 healthy children. The ANOVA test showed high ability of the regional Fuzzy SLs in low frequency bands, delta and theta, as well as alpha band for discriminating the two groups. A high classification accuracy of 95.5% was achieved for distinguishing autistic EEGs from healthy EEGs. It is concluded that the methodology presented in this paper can be used as an effective tool for diagnosis of the autism. Further, the regional Fuzzy SLs discovered in this research can be used as reliable markers in neurofeedback treatments to improve neuronal plasticity and connectivity in autistic patients.