Retinal lesions induce fast intrinsic cortical plasticity in adult mouse visual system

Neuronal activity plays an important role in the development and structural–functional maintenance of the brain as well as in its life‐long plastic response to changes in sensory stimulation. We characterized the impact of unilateral 15° laser lesions in the temporal lower visual field of the retina, on visually driven neuronal activity in the afferent visual pathway of adult mice using in situ hybridization for the activity reporter gene zif268. In the first days post‐lesion, we detected a discrete zone of reduced zif268 expression in the contralateral hemisphere, spanning the border between the monocular segment of the primary visual cortex (V1) with extrastriate visual area V2M. We could not detect a clear lesion projection zone (LPZ) in areas lateral to V1 whereas medial to V2M, agranular and granular retrosplenial cortex showed decreased zif268 levels over their full extent. All affected areas displayed a return to normal zif268 levels, and this was faster in higher order visual areas than in V1. The lesion did, however, induce a permanent LPZ in the retinorecipient layers of the superior colliculus. We identified a retinotopy‐based intrinsic capacity of adult mouse visual cortex to recover from restricted vision loss, with recovery speed reflecting the areal cortical magnification factor. Our observations predict incomplete visual field representations for areas lateral to V1 vs. lack of retinotopic organization for areas medial to V2M. The validation of this mouse model paves the way for future interrogations of cortical region‐ and cell‐type‐specific contributions to functional recovery, up to microcircuit level.     

Comparative effects of adaptation on layers II–III and V–VI neurons in cat V1

V1 is fundamentally grouped into columns that descend from layers II–III to V–VI. Neurons inherent to visual cortex are capable of adapting to changes in the incoming stimuli that drive the cortical plasticity. A principle feature called orientation selectivity can be altered by the presentation of non‐optimal stimulus called ‘adapter’. When triggered, LGN cells impinge upon layer IV and further relay the information to deeper layers via layers II–III. Using different adaptation protocols, neuronal plasticity can be investigated. Superficial neurons in area V1 are well acknowledged to exhibit attraction and repulsion by shifting their tuning peaks when challenged by a non‐optimal stimulus called ‘adapter’. Layers V–VI neurons in spite of partnering layers II–III neurons in cortical computation have not been explored simultaneously toward adaptation. We believe that adaptation not only affects cells specific to a layer but modifies the entire column. In this study, through simultaneous multiunit recordings in anesthetized cats using a multichannel depth electrode, we show for the first time how layers V–VI neurons (1000–1200 μm) along with layers II–III neurons (300–500 μm) exhibit plasticity in response to adaptation. Our results demonstrate that superficial and deeper layer neurons react synonymously toward adapter by exhibiting similar behavioral properties. The neurons displayed similar amplitude of shift and maintained equivalent sharpness of Gaussian tuning peaks before and the following adaptation. It appears that a similar mechanism, belonging to all layers, is responsible for the analog outcome of the neurons’ experience with adapter.     

Contribution of estrogen receptor subtypes,ERα, ERβ, and GPER1 in rapid estradiol‐mediated enhancement of hippocampal synaptic transmission in mice

Estradiol rapidly modulates hippocampal synaptic plasticity and synaptic transmission; however, the contribution of the various estrogen receptors to rapid changes in synaptic function is unclear. This study examined the effect of estrogen receptor selective agonists on hippocampal synaptic transmission in slices obtained from 3–5‐month‐old wild type (WT), estrogen receptor alpha (ERαKO), and beta (ERβKO) knockout female ovariectomized mice. Hippocampal slices were prepared 10–16 days following ovariectomy and extracellular excitatory postsynaptic field potentials were recorded from CA3‐CA1 synaptic contacts before and following application of 17β‐estradiol‐3‐benzoate (EB, 100 pM), the G‐protein estrogen receptor 1 (GPER1) agonist G1 (100 nM), the ERα selective agonist propyl pyrazole triol (PPT, 100 nM), or the ERβ selective agonist diarylpropionitrile (DPN, 1 µM). Across all groups, EB and G1 increased the synaptic response to a similar extent. Furthermore, prior G1 application occluded the EB‐mediated enhancement of the synaptic response and the GPER1 antagonist, G15 (100 nM), inhibited the enhancement of the synaptic response induced by EB application. We confirmed that the ERα and ERβ selective agonists (PPT and DPN) had effects on synaptic responses specific to animals that expressed the relevant receptor; however, PPT and DPN produced only a small increase in synaptic transmission relative to EB or the GPER1 agonist. We demonstrate that the increase in synaptic transmission is blocked by inhibition of extracellular signal‐regulated kinase (ERK) activity. Furthermore, EB was able to increase ERK activity regardless of genotype. These results suggest that ERK activation and enhancement of synaptic transmission by EB involves multiple estrogen receptor subtypes. © 2015 Wiley Periodicals, Inc.     

Postnatal accumulation of intermediate filaments in the cat and human primary visual cortex

A principal characteristic of the mammalian visual system is its high capacity for plasticity in early postnatal development during a time commonly referred to as the critical period. The progressive diminution of plasticity with age is linked to the emergence of a collection of molecules called molecular brakes that reduce plasticity and stabilize neural circuits modified by earlier visual experiences. Manipulation of braking molecules either pharmacologically or though experiential alteration enhances plasticity and promotes recovery from visual impairment. The stability of neural circuitry is increased by intermediate filamentous proteins of the cytoskeleton such as neurofilaments and α‐internexin. We examined levels of these intermediate filaments within cat and human primary visual cortex (V1) across development to determine whether they accumulate following a time course consistent with a molecular brake. In both species, levels of intermediate filaments increased considerably throughout early postnatal life beginning shortly after the peak of the critical period, with the highest levels measured in adults. Neurofilament phosphorylation was also observed to increase throughout development, raising the possibility that posttranslational modification by phosphorylation reduces plasticity due to increased protein stability. Finally, an approach to scale developmental time points between species is presented that compares the developmental profiles of intermediate filaments between cats and humans. Although causality between intermediate filaments and plasticity was not directly tested in this study, their accumulation relative to the critical period indicates that they may contribute to the decline in plasticity with age, and may also constrain the success of treatments for visual disorders applied in adulthood. J. Comp. Neurol. 523:2111–2126, 2015. © 2015 Wiley Periodicals, Inc.     

Speech acquisition predicts regions of enhanced cortical response to auditory stimulation in autism spectrum individuals

A continuum of phenotypes makes up the autism spectrum (AS). In particular, individuals show large differences in language acquisition, ranging from precocious speech to severe speech onset delay. However, the neurological origin of this heterogeneity remains unknown. Here, we sought to determine whether AS individuals differing in speech acquisition show different cortical responses to auditory stimulation and morphometric brain differences. Whole-brain activity following exposure to non-social sounds was investigated. Individuals in the AS were classified according to the presence or absence of Speech Onset Delay (AS-SOD and AS-NoSOD, respectively) and were compared with IQ-matched typically developing individuals (TYP). AS-NoSOD participants displayed greater task-related activity than TYP in the inferior frontal gyrus and peri-auditory middle and superior temporal gyri, which are associated with language processing. Conversely, the AS-SOD group only showed enhanced activity in the vicinity of the auditory cortex. We detected no differences in brain structure between groups. This is the first study to demonstrate the existence of differences in functional brain activity between AS individuals divided according to their pattern of speech development. These findings support the Trigger-threshold-target model and indicate that the occurrence of speech onset delay in AS individuals depends on the location of cortical functional reallocation, which favors perception in AS-SOD and language in AS-NoSOD.     

The antidepressant mechanism of action of vagus nerve stimulation: Evidence from preclinical studies

Vagus nerve stimulation (VNS) is a proposed neuromodulatory treatment for medically refractory major depression. Although VNS is already used in clinical practice, the underlying mechanism of action remains unknown. The present review provides an overview of the preclinical VNS studies in view of two major hypotheses in depression research: the monoaminergic and the neural plasticity hypothesis of depression.     

The selective noradrenergic reuptake inhibitor reboxetine restores spatial learning deficits,biochemical changes,and hippocampal synaptic plasticity in an animal model of depression

Depression is a major psychiatric illness that is associated with cognitive dysfunctions. The underlying mechanism of depression‐associated memory impairment is unclear. Previously, we showed altered hippocampal synaptic plasticity in an animal model of depression. Although several antidepressants are beneficial in the treatment of depression, very little is known about the effects of these drugs on depression‐associated learning and memory deficits. Prolonged antidepressant treatment might contribute to neuroplastic changes required for clinical outcomes. Accordingly, we evaluated the effect of chronic reboxetine (a selective noradrenergic reuptake inhibitor) treatment on depression‐induced reduced hippocampal synaptic plasticity, neurotransmitter levels, and spatial learning and memory impairments. Depression was induced in male Wistar rats by the administration of clomipramine from postnatal days 8 to 21, and these rats were treated with reboxetine in adulthood. The neonatal clomipramine administration resulted in impaired hippocampal long‐term potentiation (LTP), decreased hippocampal cholinergic activity and monoamine levels, and poor performance in a partially baited eight‐arm radial maze task. Chronic reboxetine treatment restored the hippocampal LTP, acetylcholinesterase activity, and levels of biogenic amines and ameliorated spatial learning and memory deficits in the depressed state. Thus, restoration of hippocampal synaptic plasticity might be a cellular mechanism underlying the beneficial effect of reboxetine in depression‐associated cognitive deficits. This study furthers the existing understanding of the effects of antidepressants on learning, memory, and synaptic plasticity and could ultimately assist in the development of better therapeutic strategies to treat depression and associated cognitive impairments. © 2014 Wiley Periodicals, Inc.     

PEGylation enhances the therapeutic potential for insulin-like growth factor I in central nervous system disorders

Objective

Due to its potent neurotrophic activity, insulin-like growth factor I (IGF-I) has been proposed many times for therapeutic application in disorders of the central nervous system (CNS). However, insufficient brain delivery to yield beneficial central without peripheral side effects have prevented clinical development in most instances.

Design

We recently reported the generation of a polyethylene-glycol modified IGF-I variant (PEG-IGF-I) with prolonged half-life and less acute side effects, but with fully maintained slow anabolic activity. Here we investigated if these beneficial properties result in improved brain availability of the drug, thereby reaching therapeutically relevant steady-state concentrations to elicit beneficial effects on neuronal function.

Results

After a single subcutaneous injection, PEG-IGF-I reached much higher steady-state levels in brain tissue and cerebrospinal fluid compared with IGF-I. Two weeks treatment with PEG-IGF-I was sufficient to modulate brain plasticity processes, as judged by changes in synaptic proteins and related animal behavior. Furthermore, chronic treatment of a mouse model of brain amyloidosis with PEG-IGF-I reverted deficits in insulin/IGF-I signaling, synaptic proteins and cognitive performance.

Conclusions

Our data generate the therapeutic potential for PEG-IGF-I to treat CNS disorders by systemic drug application, and in addition scientifically support its application in disorders of synaptic function and neuronal development.