Hyper-Connectivity and Hyper-Plasticity in the Medial Prefrontal Cortex in the Valproic Acid Animal Model of Autism

The prefrontal cortex has been extensively implicated in autism to explain deficits in executive and other higher-order functions related to cognition, language, sociability and emotion. The possible changes at the level of the neuronal microcircuit are however not known. We studied microcircuit alterations in the prefrontal cortex in the valproic acid rat model of autism and found that the layer 5 pyramidal neurons are connected to significantly more neighbouring neurons than in controls. These excitatory connections are more plastic displaying enhanced long-term potentiation of the strength of synapses. The microcircuit alterations found in the prefrontal cortex are therefore similar to the alterations previously found in the somatosensory cortex. Hyper-connectivity and hyper-plasticity in the prefrontal cortex implies hyper-functionality of one of the highest order processing regions in the brain, and stands in contrast to the hypo-functionality that is normally proposed in this region to explain some of the autistic symptoms. We propose that a number of deficits in autism such as sociability, attention, multi-tasking and repetitive behaviours, should be re-interpreted in the light of a hyper-functional prefrontal cortex

Hyperconnectivity of Local Neocortical Microcircuitry Induced by Prenatal Exposure to Valproic Acid

Exposure to valproic acid (VPA) during embryogenesis can cause several teratogenic effects, including developmental delays and in particular autism in humans if exposure occurs during the third week of gestation. We examined the postnatal effects of embryonic exposure to VPA on microcircuit properties of juvenile rat neocortex using in vitro electrophysiology. We found that a single prenatal injection of VPA on embryonic day 11.5 causes a significant enhancement of the local recurrent connectivity formed by neocortical pyramidal neurons. The study of the biophysical properties of these connections revealed weaker excitatory synaptic responses. A marked decrease of the intrinsic excitability of pyramidal neurons was also observed. Furthermore, we demonstrate a diminished number of putative synaptic contacts in connection between layer 5 pyramidal neurons. Local hyperconnectivity may render cortical modules more sensitive to stimulation and once activated, more autonomous, isolated, and more difficult to command. This could underlie some of the core symptoms observed in humans prenatally exposed to valproic aci

The Intense World Syndrome – an Alternative Hypothesis for Autism

Autism is a devastating neurodevelopmental disorder with a polygenetic predisposition that seems to be triggered by multiple environmental factors during embryonic and/or early postnatal life. While significant advances have been made in identifying the neuronal structures and cells affected, a unifying theory that could explain the manifold autistic symptoms has still not emerged. Based on recent synaptic, cellular, molecular, microcircuit, and behavioral results obtained with the valproic acid (VPA) rat model of autism, we propose here a unifying hypothesis where the core pathology of the autistic brain is hyper-reactivity and hyper-plasticity of local neuronal circuits. Such excessive neuronal processing in circumscribed circuits is suggested to lead to hyper-perception, hyper-attention, and hyper-memory, which may lie at the heart of most autistic symptoms. In this view, the autistic spectrum are disorders of hyper-functionality, which turns debilitating, as opposed to disorders of hypo-functionality, as is often assumed. We discuss how excessive neuronal processing may render the world painfully intense when the neocortex is affected and even aversive when the amygdala is affected, leading to social and environmental withdrawal. Excessive neuronal learning is also hypothesized to rapidly lock down the individual into a small repertoire of secure behavioral routines that are obsessively repeated. We further discuss the key autistic neuropathologies and several of the main theories of autism and re-interpret them in the light of the hypothesized Intense World Syndrome

Multitalented Synthetic Antimicrobial Peptides and Their Antibacterial, Antifungal and Antiviral Mechanisms

: Despite the great strides in healthcare during the last century, some challenges still remained unanswered. The development of multi-drug resistant bacteria, the alarming growth of fungal infections, the emerging/re-emerging of viral diseases are yet a worldwide threat. Since the discovery of natural antimicrobial peptides able to broadly hit several pathogens, peptide-based therapeutics have been under the lenses of the researchers. This review aims to focus on synthetic peptides and elucidate their multifaceted mechanisms of action as antiviral, antibacterial and antifungal agents. Antimicrobial peptides generally affect highly preserved structures, e.g., the phospholipid membrane via pore formation or other constitutive targets like peptidoglycans in Gram-negative and Gram-positive bacteria, and glucan in the fungal cell wall. Additionally, some peptides are particularly active on biofilm destabilizing the microbial communities. They can also act intracellularly, e.g., on protein biosynthesis or DNA replication. Their intracellular properties are extended upon viral infection since peptides can influence several steps along the virus life cycle starting from viral receptor-cell interaction to the budding. Besides their mode of action, improvements in manufacturing to increase their half-life and performances are also taken into consideration together with advantages and impairments in the clinical usage. Thus far, the progress of new synthetic peptide-based approaches is making them a promising tool to counteract emerging infections

A critical period for auditory thalamocortical connectivity.

1 1 8 9 a r t I C l e S Neural circuits are shaped by experience during periods of heightened brain plasticity in early life 1,2 . Children raised in an English-speaking environment easily distinguish between the phonemes /la/ and /ra/, whereas those growing up in Japan find it increasingly difficult 3 . Passive exposure of young rodents to a variety of sound features reveals a cascading series of developmental windows that open and close shortly after hearing onset to define the persistent and specific influences of early experience on the functional organization of auditory cortex Motivated by the well known binocular interactions shaped by experience in developing visual cortex 7-9 , we used in vivo neurophysiological recordings to determine whether mouse A1 also exhibits a critical period for tonotopic map plasticity induced through passive tone exposure, and whether such plasticity is present in the auditory thalamus (ventral medial geniculate body, MGBv). We then isolated the connection between MGBv and primary auditory cortex (A1) (ref. 10) in an acute brain slice preparation 11 and used voltage-sensitive dye imaging (VSDI) techniques in vitro. We mapped A1 responses to electrical stimulation of discrete sites in MGBv across early postnatal days (P8-20), following tone-rearing or gene manipulation. Our results reveal a critical period for acoustically driven topographic plasticity at thalamocortical connections in mouse A1. RESULTS Tone exposure modifies tonotopic maps in A1, but not MGBv The auditory system is tonotopically organized 10 such that tones of similar frequency activate neighboring neurons at each station along the pathway. Given that rats show experience-dependent tonotopic map reorganization following passive tone exposure during the second postnatal week 2,12 , we first used high-density in vivo mapping to delineate A1 tonotopy in young adult mice 13 that were reared either in typical acoustic environments To determine whether remapping in A1 could be explained by a shifted frequency representation in the principal subcortical input source, we also examined best frequency distributions in the MGBv. We inserted a multichannel silicon probe at an angle that matched the plane of section used in subsequent thalamocortical slice experiment

Enhanced Long-Term Microcircuit Plasticity in the Valproic Acid Animal Model of Autism

A single intra-peritoneal injection of valproic acid (VPA) on embryonic day (ED) 11.5 to pregnant rats has been shown to produce severe autistic-like symptoms in the offspring. Previous studies showed that the microcircuitry is hyperreactive due to hyperconnectivity of glutamatergic synapses and hyperplastic due to over-expression of NMDA receptors. These changes were restricted to the dimensions of a minicolumn (<50 μm). In the present study, we explored whether Long Term Microcircuit Plasticity (LTMP) was altered in this animal model. We performed multi-neuron patch-clamp recordings on clusters of layer 5 pyramidal cells in somatosensory cortex brain slices (PN 12–15), mapped the connectivity and characterized the synaptic properties for connected neurons. Pipettes were then withdrawn and the slice was perfused with 100 μM sodium glutamate in artificial cerebrospinal fluid in the recording chamber for 12 h. When we re-patched the same cluster of neurons, we found enhanced LTMP only at inter-somatic distances beyond minicolumnar dimensions. These data suggest that hyperconnectivity is already near its peak within the dimensions of the minicolumn in the treated animals and that LTMP, which is normally restricted to within a minicolumn, spills over to drive hyperconnectivity across the dimensions of a minicolumn. This study provides further evidence to support the notion that the neocortex is highly plastic in response to new experiences in this animal model of autism

Abnormal fear conditioning and amygdala processing in an animal model of autism

A core feature of autism spectrum disorders is the impairment in social interactions. Among other brain regions, a deficit in amygdala processing has been suggested to underlie this impairment, but whether the amygdala is processing fear abnormally in autism, is yet not clear. We used the valproic acid (VPA) rat model of autism to (a) screen for autism-like symptoms in rats, (b) test for alterations in amygdala-dependent fear processing, and (c) evaluate neuronal reactivity and synaptic plasticity in the lateral amygdala by means of in vitro single-cell electrophysiological recordings. VPA-treated animals displayed several symptoms common to autism, among them impaired social interactions and increased repetitive behaviors. Furthermore, VPA-treated rats were more anxious and exhibited abnormally high and longer lasting fear memories, which were overgeneralized and harder to extinguish. On the cellular level, the amygdala was hyperreactive to electrical stimulation and displayed boosted synaptic plasticity as well as a deficit in inhibition. We show for the first time enhanced, overgeneralized and resistant conditioned fear memories in an animal model of autism. Such hyperfear could be caused by the hyperreactivity and hyperplasticity found in the lateral amygdala, which may in turn be due to a deficit in the inhibitory system of the amygdala. We hypothesize an 'aversive world' syndrome that could, even if not a primary cause of the disorder itself, underlie some core symptoms in autism, such as impairments in social interactions and resistance to rehabilitatio

SOSIALISASI PENCEGAHAN STUNTING DAN TALKSHOW “SEDIKIT LEBIH BEDA LEBIH BAIK DARIPADA SEDIKIT LEBIH BAIK” DESA PARIT KECAMATAN CEMPAGA HULU KABUPATEN KOTAWARINGIN TIMUR

Kuliah Kerja Nyata merupakan salah satu program dan kegiatan dalam rangka menciptakan dan menumbuhkan jiwa pengabdian pada diri mahasiswa dengan menerapkan berbagai ilmu dan teori yang didapatkan dibangku perkuliahan sehingga dapat diterapkan dan bermanfaat khususnya bagi masyarakat pedesaan. Mahasiswa harus mampu memberikan kontribusi kepada desa untuk menuju desa yang mandiri dan berkelanjutan. Ada 4 sub tema yang sudah ditetapkan oleh Lembaga Penelitian dan Pengabdian Kepada Masyarakat kepada mahasiswa KKN-T Mandiri Edisi Khusus Tahun 2022. Salah satu implementasi dari sub tema tersebut adalah program kerja, sosialisasi pencegahan stunting dan talkshow “Sedikit Lebih Beda Lebih Baik Daripada Sedikit Lebih Baik” Desa Parit Kecamatan Cempaga Hulu Kabupaten Kotawaringin Timur. Tujuan dilaksanakannya Program kerja ini untuk menjadikan warga desa terutama para remaja menjadi lebih inovatif dan sehat serta membantu perangkat desa untuk memaksimalkan pelayanan kepada masyaraka