Closed-loop brain stimulation augments fear extinction in male rats.

Dysregulated fear reactions can result from maladaptive processing of trauma-related memories. In post-traumatic stress disorder (PTSD) and other psychiatric disorders, dysfunctional extinction learning prevents discretization of trauma-related memory engrams and generalizes fear responses. Although PTSD may be viewed as a memory-based disorder, no approved treatments target pathological fear memory processing. Hippocampal sharp wave-ripples (SWRs) and concurrent neocortical oscillations are scaffolds to consolidate contextual memory, but their role during fear processing remains poorly understood. Here, we show that closed-loop, SWR triggered neuromodulation of the medial forebrain bundle (MFB) can enhance fear extinction consolidation in male rats. The modified fear memories became resistant to induced recall (i.e., 'renewal' and 'reinstatement') and did not reemerge spontaneously. These effects were mediated by D2 receptor signaling-induced synaptic remodeling in the basolateral amygdala. Our results demonstrate that SWR-triggered closed-loop stimulation of the MFB reward system enhances extinction of fearful memories and reducing fear expression across different contexts and preventing excessive and persistent fear responses. These findings highlight the potential of neuromodulation to augment extinction learning and provide a new avenue to develop treatments for anxiety disorders.

Reinstating olfactory bulb-derived limbic gamma oscillations alleviates depression-like behavioral deficits in rodents.

Although the etiology of major depressive disorder remains poorly understood, reduced gamma oscillations is an emerging biomarker. Olfactory bulbectomy, an established model of depression that reduces limbic gamma oscillations, suffers from non-specific effects of structural damage. Here, we show that transient functional suppression of olfactory bulb neurons or their piriform cortex efferents decreased gamma oscillation power in limbic areas and induced depression-like behaviors in rodents. Enhancing transmission of gamma oscillations from olfactory bulb to limbic structures by closed-loop electrical neuromodulation alleviated these behaviors. By contrast, silencing gamma transmission by anti-phase closed-loop stimulation strengthened depression-like behaviors in naive animals. These induced behaviors were neutralized by ketamine treatment that restored limbic gamma power. Taken together, our results reveal a causal link between limbic gamma oscillations and depression-like behaviors in rodents. Interfering with these endogenous rhythms can affect behaviors in rodent models of depression, suggesting that restoring gamma oscillations may alleviate depressive symptoms.

Intelligence and executive function of school-age preterm children in function of birth weight and perinatal complication.

AIM: Assessment of intelligence and executive function in 9-10-year-old preterm children as compared to a full-term comparison group and to reveal the background of the individual differences in the outcomes by analyzing the effects of perinatal and social-economic factors. METHOD: Seventy-two preterm children (divided into two groups: 32 extremely low birth weight, 40 very low birth weight) and a matched group of 33 healthy full-term children, aged 9-10 years, were tested using the Wechsler Intelligence Scales for Children (WISC-IV) and digital versions of tasks measuring executive function. As background information perinatal variables and maternal education were entered in the analysis. RESULTS: In the WISC-IV all three groups performed in the normal range. The preterm children, particularly the ELBW subgroup, scored significantly lower than the full-term comparison group in several outcome measures. Behind the group means there were massive scatters of the individual scores. Lower maternal education, male gender, and bronchopulmonary dysplasia (BPD) increased the risk for performance deficits. CONCLUSION: Low-to-moderate risk preterm children as groups are disadvantaged in the development of intelligence and executive function as compared to healthy full-term children even until school-age. However, with appropriate protective factors they may have chances to develop comparably with their full-term, non-risk counterparts.

The Medial Septum as a Potential Target for Treating Brain Disorders Associated With Oscillopathies.

The medial septum (MS), as part of the basal forebrain, supports many physiological functions, from sensorimotor integration to cognition. With often reciprocal connections with a broad set of peers at all major divisions of the brain, the MS orchestrates oscillatory neuronal activities throughout the brain. These oscillations are critical in generating sensory and emotional salience, locomotion, maintaining mood, supporting innate anxiety, and governing learning and memory. Accumulating evidence points out that the physiological oscillations under septal influence are frequently disrupted or altered in pathological conditions. Therefore, the MS may be a potential target for treating neurological and psychiatric disorders with abnormal oscillations (oscillopathies) to restore healthy patterns or erase undesired ones. Recent studies have revealed that the patterned stimulation of the MS alleviates symptoms of epilepsy. We discuss here that stimulus timing is a critical determinant of treatment efficacy on multiple time scales. On-demand stimulation may dramatically reduce side effects by not interfering with normal physiological functions. A precise pattern-matched stimulation through adaptive timing governed by the ongoing oscillations is essential to effectively terminate pathological oscillations. The time-targeted strategy for the MS stimulation may provide an effective way of treating multiple disorders including Alzheimer's disease, anxiety/fear, schizophrenia, and depression, as well as pain.

Reading and spelling skills of prematurely born children in light of the underlying cognitive factors.

Prematurity is a serious risk factor for learning difficulties. Within the academic skills reading has the greatest impact on the prospects of the students; therefore, studying the reading skills in the risk populations is very important. The aim of our study was to investigate reading and spelling skills of prematurely born children. Our target group consisted of 8-11-year-old children (n = 23) who were born preterm with very low birthweights (VLBW). For comparison 57 full-term children (27 good readers and 30 dyslexics) were included in the study sample. To assess the reading and spelling abilities the Hungarian version of the 3DM (Dyslexia Differential Diagnosis) was used. Cognitive abilities were tested using the Hungarian adaptation of the WISC-IV and the Rey Complex Figure Test. The data were analyzed with a novel statistical approach using the R program. In the cognitive measures the mean performances of all three groups fell within the normal range. In the WISC-IV Full-scale IQ as well as in some other cognitive measures the good readers significantly outperformed both the dyslexics and the preterms. The findings of the study did not confirm our expectation that VLBW prematurity should lead to developmental disadvantages in the acquisition of reading and spelling skills since in the reading and spelling performances of the good readers and the preterms did not differ, while both the good readers and the preterms scored higher than the dyslexics. The results suggest that the cognitive assets of the preterm children contributing to their reading and spelling performances were their good spatial-visual memory, working memory, and processing speed. The identification of the cognitive mechanisms underlying reading and spelling abilities is of crucial importance for designing intervention for children with deficits in these academic skills.

[Follow-up study of extremely low birth weight preterm infants to preschool age in the light of perinatal complications]. / Az extrém kis születési súlyú koraszülöttek fejlodésének követése az óvodáskor végéig a perinatalis szövodmények tükrében.

INTRODUCTION: Owing to the rapid progress of the medical science and technology, the chances of survival of the extremely low birth weight (<1000 g) preterm babies have dramatically improved. Nevertheless, the research findings on their long-term developmental outcome are inconsistent. AIM: Our study has attempted to contribute to the understanding of the developmental mechanisms in the extremely low birth weight preterm infants and to the prediction of the developmental outcomes taking into account of the risk factors of development. METHOD: 34 preterm children who were free of any major central nervous system injury were followed up from one to 5-6 years of age. The psychomotor development of the infants was assessed at 1 and 2 years of age and, at 5-6 years of age, intelligence tests were administered to the children. Perinatal and environmental factors were included in the data analysis. RESULTS: The extremely low birth weight preterm children as a group displayed no developmental delay at any of the measurement points. The mean developmental quotients were 98.6 and 106.6 at ages 1 and 2 years, respectively. At 5-6 years of age, the mean verbal IQ was 101.4, while the mean performance IQ was 92.9. Behind the group means there was a wide range of individual variations. The most powerful contributors to the developmental outcomes were birth weight, bronchopulmonary dysplasia, intra-uterine growth retardation, gender, and maternal education. The girls had a significant advantage over the boys in language development. Verbal intelligence was hampered by intracranial hemorrhage, while intrauterine growth restriction had a similar effect on the performance IQ. CONCLUSIONS: Our results suggest that even the extremely preterm infants may have rather good chances of satisfactory mental development. However, the individual developmental prospects are influenced by a great number of domain-specific risk- and protective factors. Although at a group-level, infant psychomotor development is a significant predictor of later intelligence quotient, the rate of development may change at any age. The phenomenon of "moving risk" underscores the importance of the long-term follow-up of preterm infants. Orv Hetil. 2018; 159(41): 1672-1679.

Coding of self-motion-induced and self-independent visual motion in the rat dorsomedial striatum.

Evolutionary development of vision has provided us with the capacity to detect moving objects. Concordant shifts of visual features suggest movements of the observer, whereas discordant changes are more likely to be indicating independently moving objects, such as predators or prey. Such distinction helps us to focus attention, adapt our behavior, and adjust our motor patterns to meet behavioral challenges. However, the neural basis of distinguishing self-induced and self-independent visual motions is not clarified in unrestrained animals yet. In this study, we investigated the presence and origin of motion-related visual information in the striatum of rats, a hub of action selection and procedural memory. We found that while almost half of the neurons in the dorsomedial striatum are sensitive to visual motion congruent with locomotion (and that many of them also code for spatial location), only a small subset of them are composed of fast-firing interneurons that could also perceive self-independent visual stimuli. These latter cells receive their visual input at least partially from the secondary visual cortex (V2). This differential visual sensitivity may be an important support in adjusting behavior to salient environmental events. It emphasizes the importance of investigating visual motion perception in unrestrained animals.

Large-scale, high-density (up to 512 channels) recording of local circuits in behaving animals.

Monitoring representative fractions of neurons from multiple brain circuits in behaving animals is necessary for understanding neuronal computation. Here, we describe a system that allows high-channel-count recordings from a small volume of neuronal tissue using a lightweight signal multiplexing headstage that permits free behavior of small rodents. The system integrates multishank, high-density recording silicon probes, ultraflexible interconnects, and a miniaturized microdrive. These improvements allowed for simultaneous recordings of local field potentials and unit activity from hundreds of sites without confining free movements of the animal. The advantages of large-scale recordings are illustrated by determining the electroanatomic boundaries of layers and regions in the hippocampus and neocortex and constructing a circuit diagram of functional connections among neurons in real anatomic space. These methods will allow the investigation of circuit operations and behavior-dependent interregional interactions for testing hypotheses of neural networks and brain function.

Direct projection from the visual associative cortex to the caudate nucleus in the feline brain.

Recent morphological and physiological studies support the assumption that the extrageniculate ascending tectofugal pathways send visual projection to the caudate nucleus (CN) in amniotes. In the present study we investigate the anatomical connection between the visual associative cortex along the anterior ectosylvian sulcus (AES) and the CN in adult domestic cats. An anterograde tracer - fluoro-dextrane-amine - was injected into the AES cortex. The distribution of labeled axons was not uniform in the CN. The majority of labeled axons and terminal like puncta was found only in a limited area in the dorsal part of the CN between the coordinates anterior 12-15. Furthermore, a retrograde tracer - choleratoxin-B - was injected into the dorsal part of the CN between anterior 12 and 13. We detected a large number of labeled neurons in the fundus and the dorsal part of the AES between the coordinates anterior 12-14. Based upon our recent results we argue that there is a direct monosynaptic connection between the visual associative cortex along the AES and the CN. Beside the posterior thalamus, the AES cortex should also participate in the transmission of the tectal visual information to the CN. This pathway is likely to convey complex information containing both sensory and motor components toward the basal ganglia, which supports their integrative function in visuomotor actions such as motion and novelty detection and saccade generation.

Lack of mutation of the folliculin gene in sporadic chromophobe renal cell carcinoma and renal oncocytoma.

Germline mutation of the folliculin gene (BHD) at chromosome 17p11.2 is associated with the development of multiplex hamartomas of the hair follicles, chromophobe renal cell carcinomas (RCC) and renal oncocytomas (RO). We have analyzed the folliculin gene with sequencing for mutations and the chromosome 17p11.2 with microsatellites for allelic changes in sporadic ROs and chromophobe RCCs. Allelic loss at chromosome 17 was seen in 8 of 8 chromophobe RCCs whereas none of the 8 RO showed alteration at this chromosomal region. Sequencing all exons from genomic DNA failed to disclose mutations of the folliculin gene in any of the tumors. We found a single nucleotide polymorphism (SNP) of G/A (nt 74) at the first exon in the untranslated region of the folliculin gene. We did not find a correlation between the SNP G/A or loss of the G allele and the expression level of either splice variants of the folliculin gene. Our data suggest the folliculin gene does not play a role in the tumorigenesis of sporadic chromophobe RCCs and renal oncocytomas.

Frequent allelic changes at chromosome 7q34 but lack of mutation of the BRAF in papillary renal cell tumors.

We have analyzed the BRAF locus on chromosome 7q34 with microsatellites for allelic changes and exons 11 and 15 of the BRAF with sequencing for mutations in 50 kidney cancers including 20 papillary, 15 conventional and 15 chromophobe renal cell carcinomas (RCC). Allelic changes at the BRAF locus were seen in 16 of the 20 papillary, 3 of the 15 conventional RCCs and 2 of the 15 chromophobe RCCs. Sequencing failed to disclose mutations in exons 11 and 15 of the BRAF gene in any of the tumors. Our data indicate that BRAF mutation does not play a role in the development of renal cell tumors.

A combined electrophysiological and behavioural study for the assessment of activity-dependent changes in mice.

Activity-dependent adaptive changes in the nervous system involve structural and functional changes in the cortical circuitry. In this work the cortical function was studied by repeated recording of the somatosensory and motor potentials evoked by whisker deflections after altered sensory-motor experience in adult mice. The latencies of motor and somatosensory evoked potentials were found to shorten, while their amplitudes decreased, after a behavioural challenge involving the vibrissal apparatus. Sensory deprivation achieved by whisker trimming resulted in a partial reversal of the changes observed after increased activity. The derived parameters imply that cortical information processing speeds up as a result of experience, while decreased activity has the opposite effect. The methods used throughout the experiment were minimally invasive, and thus proved to be sufficient for the long-term follow-up of cortical functions.