An increasing number of studies show that selective serotonin reuptake inhibitors (SSRIs) exert their therapeutic action, at least in part, by amplifying the influence of the living environment on mood. As a consequence, when administered in a favorable environment, SSRIs lead to a reduction of symptoms, but in stressful conditions, they show limited efficacy. Therefore, novel therapeutic approaches able to neutralize the influence of the stressful environment on treatment are needed. The aim of our study was to test whether, in a mouse model of depression, the combined administration of SSRI fluoxetine and metformin, a drug able to improve the metabolic profile, counteracts the limited efficacy of fluoxetine alone when administered in stressful conditions. Indeed, metabolic alterations are associated to both the onset of major depression and the antidepressant efficacy. To this goal, adult C57BL/6 male mice were exposed to stress for 6 weeks; the first two weeks was aimed at generating a mouse model of depression. During the remaining 4 weeks, mice received one of the following treatments: vehicle, fluoxetine, metformin, or a combination of fluoxetine and metformin. We measured liking- and wanting-type anhedonia as behavioral phenotypes of depression and assessed the expression levels of selected genes involved in major depressive disorder and antidepressant response in the dorsal and ventral hippocampus, which are differently involved in the depressive symptomatology. The combined treatment was more effective than fluoxetine alone in ameliorating the depressive phenotype after one week of treatment. This was associated to an increase in IGF2 mRNA expression and enhanced long-term potentiation, specifically in the dorsal hippocampus, at the end of treatment. Overall, the present results show that, when administered in stressful conditions, the combined fluoxetine and metformin treatment may represent a more effective approach than fluoxetine alone in a short term. Finally, our findings highlight the relevance of polypharmacological strategy as effective interventions to increase the efficacy of the antidepressant drugs currently available.

Silvia Poggini

Maria Teresa Golia

Silvia Alboni

Giampaolo Milior

Livio Pep&#x00E8; Sciarria

Aurelia Viglione

Gloria Matte Bon

Nicoletta Brunello

Stefano Puglisi-Allegra

Cristina Limatola

Laura Maggi

Igor Branchi

Combined Fluoxetine and Metformin Treatment Potentiates Antidepressant Efficacy Increasing IGF2 Expression in the Dorsal Hippocampus

Prenatal stress (PS) has long-term sequelae for the morphological and functional status of the central nervous system of the progeny. A PS-induced proinflammatory status of the organism may result in an impairment of both hippocampal synaptic plasticity and hippocampus-dependent memory formation in adults. We addressed here the question of how PS-induced alterations in the immune response in young and old mice may contribute to changes in hippocampal function in aging. Immune stimulation (via LPS injection) significantly affected the ability of the hippocampal CA3-CA1 synapse of PS mice to undergo long-term potentiation (LTP). Elevated corticosterone level in the blood of aged PS mice that is known to influence LTP magnitude indicates a chronic activation of the HPA axis due to the in utero stress exposure. We investigated the contribution of adrenergic receptors to the modulation of hippocampal synaptic plasticity of aged mice and found that impaired LTP in the PS-LPS group was indeed rescued by application of isoproterenol (a nonspecific noradrenergic agonist). Further exploration of the mechanisms of the observed phenomena will add to our understanding of the interaction between PS and proinflammatory immune activation and its contribution to the functional and structural integrity of the aging brain.

Gayane Grigoryan

Niklas Lonnemann

Martin Korte

Immune Challenge Alters Reactivity of Hippocampal Noradrenergic System in Prenatally Stressed Aged Mice

Experience plays an essential role in building brain architecture after birth. The question we address in this paper is what happens to brain and behavior when a young child is deprived of key experiences during critical periods of brain development. We focus in particular on the consequences of institutional rearing, with implication for the tens of millions of children around the world who from an early age experience profound psychosocial deprivation. Evidence is clear that deprivation can lead to a host of both short- and long-term consequences, including perturbations in brain structure and function, changes at cellular and molecular levels, and a plethora of psychological and behavioral impairments.

Charles A. Nelson

Charles H. Zeanah

Nathan A. Fox

How Early Experience Shapes Human Development: The Case of Psychosocial Deprivation

Transcranial Direct Current Stimulation (tDCS) is an emerging tool to improve upper limb motor functions after stroke acquired in adulthood; however, there is a paucity of reports on its efficacy for upper limb motor rehabilitation in congenital or early-acquired stroke. In this pilot study we have explored, for the first time, the immediate effects, and their short-term persistence, of a single application of anodal tDCS on chronic upper limb motor disorders in children and young individuals with Unilateral Cerebral Palsy (UCP). To this aim, in a crossover sham-controlled study, eight subjects aged 10-28 years with UCP underwent two sessions of active and sham tDCS. Anodal tDCS (1.5&#x2009;mA, 20&#x2009;min) was delivered over the primary motor cortex (M1) of the ipsilesional hemisphere. Results showed, only following the active stimulation, an immediate improvement in unimanual gross motor dexterity of hemiplegic, but not of nonhemiplegic, hand in Box and Block test (BBT). Such improvement remained stable for at least 90 minutes. Performance of both hands in Hand Grip Strength test was not modified by anodal tDCS. Improvement in BBT was unrelated to participants&#x2019; age or lesion size, as revealed by MRI data analysis. No serious adverse effects occurred after tDCS; some mild and transient side effects (e.g., headache, tingling, and itchiness) were reported in a limited number of cases. This study provides an innovative contribution to scientific literature on the efficacy and safety of anodal tDCS in UCP. This trial is registered with <a target="_blank" href="https://clinicaltrials.gov/ct2/show/NCT03137940">NCT03137940</a>.

Emanuela Inguaggiato

Nadia Bolognini

Simona Fiori

Giovanni Cioni

Transcranial Direct Current Stimulation (tDCS) in Unilateral Cerebral Palsy: A Pilot Study of Motor Effect

Depressive symptoms are common in individuals with mild cognitive impairment (MCI) who have an increased risk of dementia. It is currently unclear whether the pattern of spontaneous brain activity in patients with MCI differs between subjects with and without depressive symptoms. The current study sought to investigate the features of spontaneous brain activity in MCI patients with depressive symptoms (D-MCI) using coherence regional homogeneity (CReHo) analysis with resting-state functional magnetic resonance imaging (rsfMRI). We obtained rsfMRI data in 16 MCI patients with depressive symptoms and 18 nondepressed MCI patients (nD-MCI) using a 3&#x2009;T scanner. Statistical analyses were performed to determine the regions in which ReHo differed between the two groups in specific frequency bands, slow-4 (0.027&#x2013;0.073&#x2009;Hz) and slow-5 (0.010&#x2013;0.027&#x2009;Hz), and typical bands (0.01&#x2013;0.08&#x2009;Hz). Correlation analyses were performed between the CReHo index of these regions and clinical variables to evaluate the relationship between CReHo and pathophysiological measures in the two groups. Our results showed that D-MCI patients exhibited significantly higher CReHo in the left Heschl&#x2019;s gyrus and left thalamus and lower CReHo in the left postcentral gyrus in the typical frequency band. In the slow-4 frequency band, D-MCI patients showed significantly higher CReHo in the left Heschl&#x2019;s gyrus and left thalamus. In the slow-5 frequency band, D-MCI patients exhibited significantly lower CReHo in the superior medial prefrontal gyrus. In addition, the results revealed that CReHo values in the left thalamus were positively correlated with Hamilton Depression Rating Scale (HAMD) scores in D-MCI patients. These results suggest that the sensorimotor network may be one of the main pathophysiological factors in D-MCI.

Xiaozheng Liu

Yunhai Tu

Yirou Zang

Aiqin Wu

Zhongwei Guo

Jiawei He

Disrupted Regional Spontaneous Neural Activity in Mild Cognitive Impairment Patients with Depressive Symptoms: A Resting-State fMRI Study

Objective. Neuropathic pain after brachial plexus injury remains an increasingly prevalent and intractable disease due to inadequacy of satisfactory treatment strategies. A detailed mapping of cortical regions concerning the brain plasticity was the first step of therapeutic intervention. However, the specific mapping research of brachial plexus pain was limited. We aimed to provide some localization information about the brain plasticity changes after brachial plexus pain in this preliminary study. Methods. 24 Sprague-Dawley rats received complete brachial plexus avulsion with neuropathic pain on the right forelimb successfully. Through functional imaging of both resting-state and block-design studies, we compared the amplitude of low-frequency fluctuations (ALFF) of premodeling and postmodeling groups and the changes of brain activation when applying sensory stimulation. Results. The postmodeling group showed significant decreases on the mechanical withdrawal threshold (MWT) in the bilateral hindpaws and thermal withdrawal latency (TWL) in the left hindpaw than the premodeling group (<svg xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg" width="19.289pt" style="vertical-align:-0.6370001pt" id="M1" height="9.2729pt" version="1.1" viewBox="-0.0498162 -8.6359 19.289 9.2729"><g transform="matrix(.013,0,0,-0.013,0,0)"><path id="g113-81" d="M600 480C600 590 528 650 384 650H143L137 622C222 614 225 607 210 531L130 127C113 41 106 36 23 28L17 0H294L300 28C204 36 195 42 212 127L243 284L314 263C327 263 339 263 352 264C465 271 600 337 600 480ZM508 481C508 351 402 304 329 304C289 304 265 311 250 317L295 559C302 594 310 606 323 611C335 616 350 619 367 619C455 619 508 573 508 481Z"/></g><g transform="matrix(.013,0,0,-0.013,11.658,0)"><path id="g117-91" d="M512 -3V55L134 254V256L512 456V514L75 281V230L512 -3Z"/></g></svg><svg xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg" width="21.918pt" style="vertical-align:-0.6370001pt" height="9.2729pt" version="1.1" viewBox="22.8711838 -8.6359 21.918 9.2729"><g transform="matrix(.013,0,0,-0.013,22.921,0)"><path id="g113-49" d="M241 635C89 635 35 457 35 312C35 153 89 -12 240 -12C390 -12 443 166 443 312C443 466 390 635 241 635ZM238 602C329 602 354 454 354 312C354 172 330 22 240 22C152 22 124 173 124 313S148 602 238 602Z"/></g><g transform="matrix(.013,0,0,-0.013,29.161,0)"><path id="g113-47" d="M113 -12C146 -12 170 11 170 46C170 78 146 103 114 103S58 78 58 46C58 11 82 -12 113 -12Z"/></g><g transform="matrix(.013,0,0,-0.013,32.125,0)"><use xlink:href="#g113-49"/></g><g transform="matrix(.013,0,0,-0.013,38.365,0)"><path id="g113-54" d="M153 550H386L412 615L406 623H120L82 318C104 327 142 338 184 338C294 338 347 275 347 187C347 112 305 39 221 39C160 39 119 71 97 89C88 97 80 96 71 90C59 80 50 67 49 57C48 45 52 36 66 23C80 9 123 -12 169 -12C221 -11 288 15 342 59C403 109 431 165 431 225C431 308 366 395 238 395C212 395 165 379 127 364L153 550Z"/></g></svg>). The amplitude of low-frequency fluctuations (ALFF) of the postmodeling group manifested increases in regions of the left anterodorsal hippocampus, left mesencephalic region, left dorsal midline thalamus, and so on. Decreased ALFF was observed in the bilateral entorhinal cortex compared to that of the premodeling group. The results of block-design scan showed significant differences in regions including the limbic/paralimbic system and somatosensory cortex. Conclusion. We concluded that the entorhinal-hippocampus pathway, which was part of the Papez circuit, was involved in the functional integrated areas of brachial plexus pain processing. The regions in the “pain matrix” showed expected activation when applying instant nociceptive stimulus but remained silent in the resting status. This research confirmed the involvement of cognitive function, which brought novel information to the potential new therapy for brachial plexus pain.

Shuai Wang

Zhen-zhen Ma

Ye-chen Lu

Jia-jia Wu

Xu-yun Hua

Mou-xiong Zheng

Jian-guang Xu

The Localization Research of Brain Plasticity Changes after Brachial Plexus Pain: Sensory Regions or Cognitive Regions?

About this journal

Neural Plasticity is an interdisciplinary journal dedicated to the publication of articles related to all aspects of neural plasticity, with special emphasis on its functional significance as reflected in behavior and in psychopathology.

Journal profile

Meet the editorial board

Chief Editor, Professor Baudry, is currently University Professor at Western University of Health Sciences in Pomona, CA. His research focuses on understanding the molecular/cellular mechanisms of learning and memory and neurodegeneration.

Editor spotlight

Submit to Special Issue

We currently have a number of Special Issues open for submission. Special Issues highlight emerging areas of research within a field, or provide a venue for a deeper investigation into an existing research area.

Special Issues

Author guidelines

Editorial board

Databases and indexing

Neural Plasticity - Table of contents 2019

title

Neural Plasticity is an interdisciplinary journal dedicated to the publication of articles related to all aspects of neural plasticity, with special emphasis on its functional significance as reflected in behavior and in psychopathology.

Neural Plasticity