Adult Cortex Research Articles

Ketamine induces plasticity in a norepinephrine-astroglial circuit to promote behavioral perseverance.

Transient exposure to ketamine can trigger lasting changes in behavior and mood. We found that brief ketamine exposure causes long-term suppression of futility-induced passivity in larval zebrafish, reversing the "giving-up" response that normally occurs when swimming fails to cause forward movement. Whole-brain imaging revealed that ketamine hyperactivates the norepinephrine-astroglia circuit responsible for passivity. After ketamine washout, this circuit exhibits hyposensitivity to futility, leading to long-term increased perseverance. Pharmacological, chemogenetic, and optogenetic manipulations show that norepinephrine and astrocytes are necessary and sufficient for ketamine's long-term perseverance-enhancing aftereffects. Invivo calcium imaging revealed that astrocytes in adult mouse cortex are similarly activated during futility in the tail suspension test and that acute ketamine exposure also induces astrocyte hyperactivation. The cross-species conservation of ketamine's modulation of noradrenergic-astroglial circuits and evidence that plasticity in this pathway can alter the behavioral response to futility hold promise for identifying new strategies to treat affective disorders.

Assessing plasticity in the primary sensory cortex and its relation with atypical tactile reactivity in autism: A TMS-EEG protocol.

Atypical sensory reactivity is a cardinal presentation in autism. Within the tactile domain, atypical tactile reactivity (TR) is common, it emerges early, persists into adulthood, and impedes social interaction and daily functioning. Hence, atypical TR is a key target for biological intervention to improve outcomes. Brain mechanisms informing biological interventions for atypical TR remains elusive. We previously reported hyper-plasticity in the motor cortex in autistic adults and found that repetitive transcranial magnetic stimulation (rTMS), designed to strengthen inhibitory processes in the brain, reduced hyper-plasticity. Whether the primary sensory cortex (S1) is characterized by hyper-plasticity, which may underlie atypical TR in autism is unknown. We aim to test whether hyper-plasticity in the S1 underlies atypical TR in autism, and investigate if a single session of rTMS can safely reduce hyper-plasticity in S1 in autistic adults. Plasticity will be assessed in the left S1 with integrated paired associative stimulation and electroencephalography (PAS-EEG) paradigm in 32 autistic adults and 32 age-, sex-, and intelligence quotient-matched controls. Autistic participants will be further randomized (double-blind, 1:1) to receive a single-session of either sham or active 20 Hz bilateral rTMS over the S1 and the plasticity will be re-assessed over the left S1 on the same day. Atypical TR has been identified as one of the top clinical research priorities that can influence outcome in autistic population. The study findings can be highly valuable to further elucidate the mechanism underlying atypical TR, which in turn can help with developing a mechanism-driven intervention.

Interactions between excitatory neurons and parvalbumin interneurons in V1 underlie neural mechanisms of amblyopia and visual stimulation treatment

As the main cause of visual function deficits in children and adolescents worldwide, amblyopia causes serious impairment of monocular visual acuity and stereopsis. The recovery of visual functions from amblyopia beyond the critical period is slow and incomplete due to the limited plasticity of the mature cortex; notably, visual stimulation training seems to be an effective therapeutic strategy in clinical practice. However, the precise neural basis and cellular mechanisms that underlie amblyopia and visual stimulation treatment remain to be elucidated. Using monocular deprivation in juvenile mice to model amblyopia, we employed two-photon calcium imaging and chemogenetic techniques to investigate the visual responses of individual excitatory neurons and parvalbumin (PV+) interneurons in the primary visual cortex (V1) of amblyopic mice. We demonstrate that amblyopic mice exhibit an excitation/inhibition (E/I) imbalance. Moreover, visual stimulation decreases the response of PV+ interneurons, reactivates the ocular dominance plasticity of excitatory neurons, and promotes vision recovery in adult amblyopic mice. Our results reveal a dynamic E/I balance between excitatory neurons and PV+ interneurons that may underlie the neural mechanisms of amblyopia during cortical development and visual stimulation-mediated functional recovery from adult amblyopia, providing evidence for therapeutic applications that rely on reactivating adult cortical plasticity.

A comparative neuro-study of solo or accompanied low and high boric acid doses with date molasses in adult male albino rats

Boric acid (BA) is a weak acid and the simplest compound resulting from the dissolution of boron in water. There is great competition to determine whether boron is an essential or nonessential nutrient. Date molasses is a potent type of sweetener with valuable components, such as flavonoids and phenolics, and has significant health benefits. This study investigated the neuro-essentiality and neurotoxicity of boric acid boron in adult male albino rat cortex and cerebellum brain areas and the impact of date molasses treatment. Animals were grouped into the following groups: control, low and high boric acid doses, 10 and 500 mg/kg, respectively, with or without 250 mg/kg date molasses. The results revealed the ability of BAs to cross the blood–brain barrier and accumulate in the cerebellum and cortex, revealing the ability of date molasses to decrease BA accumulation at different time intervals. Additionally, the results varied between a nonsignificant increase or decrease in calcium ion content, monoamines (norepinephrine, dopamine, and serotonin), glucose, adenosine triphosphate, malondialdehyde and glutathione, depending on the BA dose. Moreover, date molasses mitigated any unwanted BA results. In conclusion, boric acid, which is within a permissible limit, could be essential and have a neuroprotective effect, whereas at a sublethal level, it could have a neurotoxic effect. Additionally, Date molasses can have neuroprotective effects and antagonize the neurotoxic effects of boric acid through its antioxidant and scavenging effects.

Enhanced auditory responses in visual cortex of blind rats using intrinsic optical signal imaging

Functional maturation of the visual cortex is induced by visual experiences during critical periods. Blind animals and humans exhibit improved auditory abilities after losing their vision. Here we investigated the response of the visual cortex to white noise stimuli during the progression of photoreceptor degeneration in a rat model of blindness (Royal College of Surgeons [RCS] (rdy/rdy) rats). Optical coherence tomography of RCS (+/+) rats with normal visual function revealed normal photoreceptor cells, whereas 3-month-old RCS (rdy/rdy) rats demonstrated photoreceptor cell degeneration. Visual cortex responses (VCRs) to a single flash stimulus were negligible in 3-month-old photoreceptor-degenerated rats. However, VCRs with white noise stimuli were significantly increased in blind versus RCS rats (+/+). Slight changes in the intrinsic optical signals of the control rats were observed on the ventral side of the visual cortex. In contrast, responses were markedly increased throughout the visual cortex of RCS (rdy/rdy) rats. These results indicate that the visual cortex rapidly acquires auditory system function over the first 3 months of life and that the entire visual cortex, rather than just the portion close to the auditory cortex, responds to white noise.

Decreased resting-state brain function in older adults predicts enlarged representational momentum.

Representational momentum (RM) refers to the phenomenon in which an observer's judgment of the final location of a previously viewed moving target is often displaced forward in the direction of motion. This phenomenon is an adaptive mechanism that compensates for neural processing delays and is closely associated with visual cortex function. However, the impact of age-related decline of visual cortex function on the manifestations of RM remains unclear. The present study examined differences in the RM effect between older (N = 82) and younger adults (N = 74) using a cursor-positioning task. Additionally, resting-state functional magnetic resonance imaging was used to explore the potential neural substrates that underlie these differences, employing amplitude of low-frequency fluctuation (ALFF, reflecting the intensity of neural activity) and regional homogeneity (ReHo, reflecting the synchronization of neural activity) as indicators. Our findings indicate a significant increase in RM among older adults compared with younger adults. Neuroimaging data revealed a significant decrease in ALFF and ReHo within extensive regions of the visual cortex in older adults, validating age-related differences in this cortical area. More importantly, ALFF values in the bilateral visual area 3 and ReHo values in the bilateral visual area 2 in older adults exhibited a strong negative correlation with their RM effects. These results suggest that larger RM in older adults may be functional compensation for aging of the visual cortex. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Functional diversities within neurons and astrocytes in the adult rat auditory cortex revealed by single-nucleus RNA sequencing

The mammalian cerebral cortex is composed of a rich diversity of cell types. Sensory cortical cells are organized into networks that rely on their functional diversity to ultimately carry out a variety of sophisticated cognitive functions for perception, learning, and memory. The auditory cortex (AC) has been most extensively studied for its experience-dependent effects, including for perceptual learning and associative memory. Here, we used single-nucleus RNA sequencing (snRNA-seq) in the AC of the adult rat to investigate the breadth of transcriptionally diverse cell types that likely support the role of AC in experience-dependent functions. A variety of unique excitatory and inhibitory neuron subtypes were identified that harbor unique transcriptional profiles of genes with putative relevance for the adaptive neuroplasticity of cortical microcircuits. In addition, we report for the first time a diversity of astrocytes in AC that may represent functionally unique subtypes, including those that could integrate experience-dependent adult neuroplasticity at cortical synapses. Together, these results pave the way for building models of how cortical neurons work in concert with astrocytes to fulfill dynamic and experience-dependent cognitive functions.

A vector system encoding histone H3 mutants facilitates manipulations of the neuronal epigenome

The differentiation of developmental cell lineages is associated with genome-wide modifications in histone H3 methylation. However, the causal role of histone H3 methylation in transcriptional regulation and cell differentiation has been difficult to test in mammals. The experimental overexpression of histone H3 mutants carrying lysine-to-methionine (K-to-M) substitutions has emerged as an alternative tool for inhibiting the endogenous levels of histone H3 methylation at specific lysine residues. Here, we leverage the use of histone K-to-M mutants by creating Enhanced Episomal Vectors that enable the simultaneous depletion of multiple levels of histone H3 lysine 4 (H3K4) or lysine 9 (H3K9) methylation in projection neurons of the mouse cerebral cortex. Our approach also facilitates the simultaneous depletion of H3K9 and H3K27 trimethylation (H3K9me3 and H3K27me3, respectively) in cortical neurons. In addition, we report a tamoxifen-inducible Cre-FLEX system that allows the activation of mutant histones at specific developmental time points or in the adult cortex, leading to the depletion of specific histone marks. The tools presented here can be implemented in other experimental systems, such as human in vitro models, to test the combinatorial role of histone methylations in developmental fate decisions and the maintenance of cell identity.

A coordinate-based meta-analysis of grey matter volume differences between adults with obsessive-compulsive disorder (OCD) and healthy controls

According to the cortico-striato-thalamo-cortical (CSTC) model of obsessive-compulsive disorder (OCD), the striatum plays a primary role in its neuropathophysiology. Hypothesising that volumetric alterations are more pronounced in subcortical areas of patients within the CSTC circuit compared to healthy controls (HCs), we conducted a coordinate-based meta-analysis of magnetic resonance imaging (MRI) studies. We included 26 whole-brain MRI studies, comprising 3,010 subjects: 1,508 patients (788 men, 720 women; mean age: 30.26 years, SD = 8.16) and 1,502 HCs (801 men, 701 women; mean age: 29.47 years, SD = 7.88). This meta-analysis demonstrated significant grey matter volume increases in the bilateral putamen, lateral globus pallidus, left parietal cortex, right pulvinar, and left cerebellum in adults with OCD, alongside decreases in the right hippocampus/caudate, bilateral medial frontal gyri, and other cortical regions. Volume increases were predominantly observed in subcortical areas, with the exception of the left parietal cortex and cerebellar dentate, while volume decreases were primarily cortical, aside from the right hippocampus/caudate. Further exploration of these neuropathophysiological correlates could inform specific prevention and treatment strategies, advancing precision mental health in clinical applications.

Activation Characteristics Of Frontal Cortex In Older Adults During Turning

Activation Characteristics Of Frontal Cortex In Older Adults During Turning

Impact of transcranial Direct Current Stimulation on stereoscopic vision and retinal structure in adult amblyopic rodents.

The impact of visual deprivation on retinal structure is widely debated. Experimental models, like monocular deprivation through lid suture, provide insights into the consequences of lacking visual experience during development. This deprivation delays primary visual cortex (CV1) maturation due to improper neural connection consolidation, which remains plastic beyond the critical period. However, few studies have used Optical Coherence Tomography (OCT) to investigate structural alterations in the retina of animal models following monocular deprivation. Instead, some studies have focused on the ganglion cell layer using post-mortem histological techniques in amblyopia models induced by monocular deprivation. In this study, we used Cliff test to assess stereoscopic vision and spectral domain optical coherence tomography (SD-OCT) to evaluate retinal changes in an in vivo model of visual deprivation treated with Transcranial Direct Current Stimulation (tDCS). The depth perception test initially revealed differences between individuals with amblyopia and the control group. However, after 8 tDCS sessions, amblyopic subjects matched the control group's performance, which remained stable Additionally, significant changes were observed in retinal structures post-tDCS treatment. Specifically, the thickness of the Nerve Fiber Layer + Ganglion Cell Layer + Inner Plexiform Layer (NFL+GCL+IPL) increased significantly in amblyopic eyes (p<0.001). Moreover, significant retinal thickening, including the Nerve Fiber Layer + Ganglion Cell Layer + Inner Plexiform Layer (NFL+GCL+IPL) and the entire retina, was observed post-tDCS treatment (p<0.05), highlighting the critical role of tDCS in ameliorating amblyopia. Additionally, treated animals exhibited reduced thickness in the Inner Nuclear Layer (INL) and Outer Nuclear Layer (ONL). tDCS treatment effectively restores amblyopic individuals' stereoscopic vision, aligning their performance with controls, while impacting retinal structure, highlighting its potential in ameliorating amblyopia's visual deficits.

White matter connectivity linked to novel word learning in children

Children and adults are excellent word learners. Increasing evidence suggests that the neural mechanisms that allow us to learn words change with age. In a recent fMRI study from our group, several brain regions exhibited age-related differences when accessing newly learned words in a second language (L2; Takashima et al. Dev Cogn Neurosci 37, 2019). Namely, while the Teen group (aged 14–16 years) activated more left frontal and parietal regions, the Young group (aged 8–10 years) activated right frontal and parietal regions. In the current study we analyzed the structural connectivity data from the aforementioned study, examining the white matter connectivity of the regions that showed age-related functional activation differences. Age group differences in streamline density as well as correlations with L2 word learning success and their interaction were examined. The Teen group showed stronger connectivity than the Young group in the right arcuate fasciculus (AF). Furthermore, white matter connectivity and memory for L2 words across the two age groups correlated in the left AF and the right anterior thalamic radiation (ATR) such that higher connectivity in the left AF and lower connectivity in the right ATR was related to better memory for L2 words. Additionally, connectivity in the area of the right AF that exhibited age-related differences predicted word learning success. The finding that across the two age groups, stronger connectivity is related to better memory for words lends further support to the hypothesis that the prolonged maturation of the prefrontal cortex, here in the form of structural connectivity, plays an important role in the development of memory.

BCAS1-positive oligodendrocytes enable efficient cortical remyelination in multiple sclerosis.

Remyelination is a crucial regenerative process in demyelinating diseases, limiting persisting damage to the central nervous system (CNS). It restores saltatory nerve conduction and ensures trophic support of axons. In multiple sclerosis (MS) patients, remyelination has been observed in both white and grey matter and found to be more efficient in the cortex. Brain-enriched myelin-associated protein 1 (BCAS1) identifies oligodendrocyte lineage cells in the stage of active myelin formation in development and regeneration. Other than in the white matter, BCAS1+ oligodendrocytes are maintained at high densities in the cortex throughout life. Here, we investigated cortical lesions in human biopsy and autopsy tissue from patients with MS in direct comparison to demyelinating mouse models and demonstrate that following a demyelinating insult BCAS1+ oligodendrocytes in remyelinating cortical lesions shift from a quiescent to an activated, internode-forming morphology co-expressing myelin-associated glycoprotein (MAG), necessary for axonal contact formation. Noteworthy, activated BCAS1+ oligodendrocytes are found at early time points of experimental demyelination amidst ongoing inflammation. In human tissue, activated BCAS 1+ oligodendrocytes correlate with the density of myeloid cells, further supporting their involvement in an immediate regenerative response. Furthermore, studying the microscopically normal appearing non demyelinated cortex in patients with chronic MS, we find a shift from quiescent BCAS1+ oligodendrocytes to mature, myelin-maintaining oligodendrocytes, suggesting oligodendrocyte differentiation and limited replenishment of BCAS1+ oligodendrocytes in long-standing disease. We also demonstrate that part of perineuronal satellite oligodendrocytes are BCAS1+ and contribute to remyelination in human and experimental cortical demyelination. In summary, our results provide evidence from human tissue and experimental models that BCAS1+ cells in the adult cortex represent a population of pre-differentiated oligodendrocytes that rapidly react after a demyelinating insult thus enabling immediate myelin regeneration. In addition, our data suggest that limited replenishment of BCAS1+ oligodendrocytes may contribute to the remyelination failure observed in the cortex in chronic MS.

The Development of Ambiguity Processing Is Explained by an Inverted U-Shaped Curve.

Understanding the developmental trajectories for recognizing facial expressions is important for a better understanding of development of psychiatric disorders. In this study, we examined the recognition of emotional and neutral facial expressions in 93 typically developing adolescents and adults. The Emotion Intensity Rating task required participants to rate the intensity of emotional expression in happy, neutral, and sad faces on a scale from 1 to 9. A score of '5' had to be assigned to neutral faces, scores between '6' (slightly happy) and '9' (very happy) to happy faces, and scores between '4' (slightly sad) and '1' (very sad) to sad faces. Mixed effects models were used to examine the effects of age and emotion on recognition accuracy, reaction time (RT), and emotional intensity. Participants tended to misjudge neutral faces as sad. Adolescents were less accurate than adults for neutral face recognition. There were significant quadratic effects of age on accuracy (negative quadratic effect) and RT (positive quadratic effect). The most accurate and fastest performance was observed in 25- to 35-year-old subjects. This trajectory may be associated with prefrontal cortex maturation, which provides top-down control over the heightened amygdala response to ambiguity that may be misinterpreted as emotional content.

Gestational CBD Shapes Insular Cortex in Adulthood.

Many expectant mothers use CBD to alleviate symptoms like nausea, insomnia, anxiety, and pain, despite limited research on its long-term effects. However, CBD passes through the placenta, affecting fetal development and impacting offspring behavior. We investigated how prenatal CBD exposure affects the insular cortex (IC), a brain region involved in emotional processing and linked to psychiatric disorders. The IC is divided into two territories: the anterior IC (aIC), processing socioemotional signals, and the posterior IC (pIC), specializing in interoception and pain perception. Pyramidal neurons in the aIC and pIC exhibit sex-specific electrophysiological properties, including variations in excitability and the excitatory/inhibitory balance. We investigated IC's cellular properties and synaptic strength in the offspring of both sexes from mice exposed to low-dose CBD during gestation (E5-E18; 3 mg/kg, s.c.). Prenatal CBD exposure induced sex-specific and territory-specific changes in the active and passive membrane properties, as well as intrinsic excitability and the excitatory/inhibitory balance, in the IC of adult offspring. The data indicate that in utero CBD exposure disrupts IC neuronal development, leading to a loss of functional distinction between IC territories. These findings may have significant implications for understanding the effects of CBD on emotional behaviors in offspring.

Functional and structural maturation of auditory cortex from 2 months to 2 years old

BackgroundIn school-age children, the myelination of the auditory radiation thalamocortical pathway is associated with the latency of auditory evoked responses, with the myelination of thalamocortical axons facilitating the rapid propagation of acoustic information. Little is known regarding this auditory system function-structure association in infants and toddlers. Methods and ParticipantsThe present study tested the hypothesis that maturation of auditory radiation white-matter microstructure (e.g., fractional anisotropy (FA); measured using diffusion-weighted MRI) is associated with the latency of the infant auditory response (the P2m response, measured using magnetoencephalography, MEG) in a cross-sectional (N = 47, 2 to 24 months, 19 females) as well as longitudinal cohort (N = 18, 2 to 29 months, 8 females) of typically developing infants and toddlers. Of 18 longitudinal infants, 2 infants had data from 3 timepoints and 16 infants had data from 2 timepoints. ResultsIn the cross-sectional sample, non-linear maturation of P2m latency and auditory radiation diffusion measures were observed. Auditory radiation diffusion accounted for significant variance in P2m latency, even after removing the variance associated with age in both P2m latency and auditory radiation diffusion measures. In the longitudinal sample, latency and FA associations could be observed at the level of a single child. ConclusionsFindings provide strong support for the hypothesis that an increase in thalamocortical neural conduction velocity, due to increased axon diameter and/or myelin maturation, contributes to a decrease in the infant P2m auditory evoked response latency. SignificanceInfant multimodal brain imaging identifies brain mechanisms contributing to the rapid changes in neural circuit activity during the first two years of life.

Temporal dynamics of neocortical development in organotypic mouse brain cultures: a comprehensive analysis.

Murine organotypic brain slice cultures have been widely used in neuroscientific research and are offering the opportunity to study neuronal function under normal and disease conditions. Despite the broad application, the mechanisms governing the maturation of immature cortical circuits in vitro are not well understood. In this study, we present a detailed investigation into the development of the neocortex in vitro. Using a holistic approach, we studied organotypic whole hemisphere brain slice cultures from postnatal mice and tracked the development of the somatosensory area over a 5-wk period. Our analysis revealed the maturation of passive and active intrinsic properties of pyramidal cells together with their morphology, closely resembling in vivo development. Detailed multielectrode array (MEA) electrophysiological assessments and RNA expression profiling demonstrated stable network properties by 2 wk in culture, followed by the transition of spontaneous activity toward more complex patterns including high-frequency oscillations. However, culturing weeks 4 and 5 exhibited increased variability and initial signs of neuronal loss, highlighting the importance of considering developmental stages in experimental design. This comprehensive characterization is vital for understanding the temporal dynamics of the neocortical development in vitro, with implications for neuroscientific research methodologies, particularly in the investigation of diseases such as epilepsy and other neurodevelopmental disorders.NEW & NOTEWORTHY The development of the mouse neocortex in vitro mimics the in vivo development. Mouse brain cultures can serve as a model system for cortical development for the first 2 wk in vitro and as a model system for the adult cortex from 2 to 4 wk in vitro. Mouse organotypic brain slice cultures develop high-frequency network oscillations at γ frequency after 2 wk in vitro. Mouse brain cultures exhibit increased heterogeneity and variability after 4 wk in culture.

Low intensity repetitive transcranial magnetic stimulation enhances remyelination by newborn and surviving oligodendrocytes in the cuprizone model of toxic demyelination

In people with multiple sclerosis (MS), newborn and surviving oligodendrocytes (OLs) can contribute to remyelination, however, current therapies are unable to enhance or sustain endogenous repair. Low intensity repetitive transcranial magnetic stimulation (LI-rTMS), delivered as an intermittent theta burst stimulation (iTBS), increases the survival and maturation of newborn OLs in the healthy adult mouse cortex, but it is unclear whether LI-rTMS can promote remyelination. To examine this possibility, we fluorescently labelled oligodendrocyte progenitor cells (OPCs; Pdgfrα-CreER transgenic mice) or mature OLs (Plp-CreER transgenic mice) in the adult mouse brain and traced the fate of each cell population over time. Daily sessions of iTBS (600 pulses; 120 mT), delivered during cuprizone (CPZ) feeding, did not alter new or pre-existing OL survival but increased the number of myelin internodes elaborated by new OLs in the primary motor cortex (M1). This resulted in each new M1 OL producing ~ 471 µm more myelin. When LI-rTMS was delivered after CPZ withdrawal (during remyelination), it significantly increased the length of the internodes elaborated by new M1 and callosal OLs, increased the number of surviving OLs that supported internodes in the corpus callosum (CC), and increased the proportion of axons that were myelinated. The ability of LI-rTMS to modify cortical neuronal activity and the behaviour of new and surviving OLs, suggests that it may be a suitable adjunct intervention to enhance remyelination in people with MS.

Adolescent Thalamoprefrontal Inhibition Leads to Changes in Intrinsic Prefrontal Network Connectivity.

Adolescent inhibition of thalamocortical projections from postnatal days P20 to 50 leads to long-lasting deficits in prefrontal cortex function and cognition in the adult mouse. While this suggests a role of thalamic activity in prefrontal cortex maturation, it is unclear how inhibition of these projections affects prefrontal circuitry during adolescence. Here, we used chemogenetic tools to inhibit thalamoprefrontal projections in male/female mice from P20 to P35 and measured synaptic inputs to prefrontal pyramidal neurons by layer (either II/III or V/VI) and projection target (mediodorsal thalamus (MD), nucleus accumbens (NAc), or callosal prefrontal projections) 24 h later using slice physiology. We found a decrease in the frequency of excitatory and inhibitory currents in layer II/III NAc and layer V/VI MD-projecting neurons while layer V/VI NAc-projecting neurons showed an increase in the amplitude of excitatory and inhibitory currents. Regarding cortical projections, the frequency of inhibitory but not excitatory currents was enhanced in contralateral mPFC-projecting neurons. Notably, despite these complex changes in individual levels of excitation and inhibition, the overall balance between excitation and inhibition in each cell was only altered in the contralateral mPFC projections. This finding suggests homeostatic regulation occurs within subcortically but not intracortical callosal-projecting neurons. Increased inhibition of intraprefrontal connectivity may therefore be particularly important for prefrontal cortex circuit maturation. Finally, we observed cognitive deficits in the adult mouse using this narrowed window of thalamocortical inhibition.

NtZIP5A/B is involved in the regulation of Zn/Cu/Fe/Mn/Cd homeostasis in tobacco.

Plants grow in soils with varying concentrations of microelements, often in the presence of toxic metals e.g. Cd. To cope, they developed molecular mechanisms to regulate metal cross-homeostasis. Understanding underlying complex relationships is key to improving crop productivity. Recent research suggests that the Zn and Cd uptake protein NtZIP5A/B [Zinc-regulated, Iron-regulated transporter-like Proteins (ZIPs)] from tobacco (Nicotiana tabacum L. v. Xanthi) is involved in the regulation of a cross-talk between the two metals. Here, we support this conclusion by showing that RNAi-mediated silencing of NtZIP5A/B resulted in a reduction of Zn accumulation and that this effect was significantly enhanced by the presence of Cd. Our data also point to involvement of NtZIP5B in regulating a cross-talk between Cu, Fe, and Mn. Using yeast growth assays, Cu (but not Fe or Mn) was identified as a substrate for NtZIP5B. Furthermore, GUS-based analysis showed that the tissue-specific activity of the NtZIP5B promoter was different in each of the Zn-/Cu-/Fe-/Mn deficiencies applied with/without Cd. The results indicate that NtZIP5B is involved in maintaining multi-metal homeostasis under conditions of Zn, Cu, Fe, and Mn deficiency, and also in the presence of Cd. It was concluded that the protein regulates the delivery of Zn and Cu specifically to targeted different root cells depending on the Zn/Cu/Fe/Mn status. Importantly, in the presence of Cd, the activity of the NtZIP5B promoter is lost in meristematic cells and increased in mature root cortex cells, which can be considered a manifestation of a defense mechanism against its toxic effects.