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Aging is a major risk factor to develop neurodegenerative diseases and is associated with decreased buffering capacity of the proteostasis network. We investigated the significance of the unfolded protein response (UPR), a major signaling pathway activated to cope with endoplasmic reticulum (ER) stress, in the functional deterioration of the mammalian brain during aging. We report that genetic disruption of the ER stress sensor IRE1 accelerated age-related cognitive decline. In mouse models, overexpressing an active form of the UPR transcription factor XBP1 restored synaptic and cognitive function, in addition to reducing cell senescence. Proteomic profiling of hippocampal tissue showed that XBP1 expression significantly restore changes associated with aging, including factors involved in synaptic function and pathways linked to neurodegenerative diseases. The genes modified by XBP1 in the aged hippocampus where also altered. Collectively, our results demonstrate that strategies to manipulate the UPR in mammals may help sustain healthy brain aging.

Alteration in the buffering capacity of the proteostasis network is an emerging feature of Alzheimer’s disease (AD), highlighting the occurrence of endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) is the main adaptive pathway to cope with protein folding stress at the ER. Inositol requiring enzyme-1 (IRE1) is an ER-located kinase and endoribonuclease that operates as a central ER stress sensor, enabling the establishment of adaptive and repair programs through the control of the expression of the transcription factor X-Box binding protein 1 (XBP1). A polymorphism in the XBP1 promoter has been suggested as a risk factor for AD. To artificially enforce the adaptive capacity of the UPR in the AD brain, we developed strategies to express the active form of XBP1 in neurons using preclinical models. Overexpression of an active form of XBP1 in the nervous system using transgenic mice significantly reduced the load of amyloid deposits in the cerebral cortex and hippocampus and preserved synaptic and cognitive function. Moreover, local delivery of XBP1 into the hippocampus of an AD mice using adeno-associated vectors improved long-term potentiation, memory performance, and dendritic spine density. Quantitative proteomics of the hippocampus revealed that XBP1 expression corrects a large proportion of the alterations observed in the 5xFAD model, restoring the levels of several synaptic proteins and factors involved in actin cytoskeleton regulation and axonal growth. Our results illustrate the therapeutic potential of targeting UPR-dependent gene expression programs as a strategy to ameliorate AD features and sustain synaptic function.

Recessive gene mutations underlie many developmental disorders and often lead to disabling neurological problems. Here, we report identification of a homozygous c.170G>A (p.Cys57Tyr or C57Y) mutation in the gene coding for protein disulfide isomerase A3 (PDIA3, also known as ERp57), an enzyme that catalyzes formation of disulfide bonds in the endoplasmic reticulum, to be associated with syndromic intellectual disability. Experiments in zebrafish embryos show that PDIA3C57Y expression is pathogenic and causes developmental defects such as axonal disorganization as well as skeletal abnormalities. Expression of PDIA3C57Y in the mouse hippocampus results in impaired synaptic plasticity and memory consolidation. Proteomic and functional analyses reveal that PDIA3C57Y expression leads to dysregulation of cell adhesion and actin cytoskeleton dynamics, associated with altered integrin biogenesis and reduced neuritogenesis. Biochemical studies show that PDIA3C57Y has decreased catalytic activity and forms disulfide-crosslinked aggregates that abnormally interact with chaperones in the endoplasmic reticulum. Thus, rare disease gene variant can provide insight into how perturbations of neuronal proteostasis can affect the function of the nervous system.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two related neurodegenerative disorders that display overlapping features. The hexanucleotide repeat expansion GGGGCC (G4 C2 ) in C9ORF72 gene has been causally linked to both ALS and FTD emergence, thus opening a novel potential therapeutic target for disease intervention. The main driver of C9ORF72 pathology is the disruption of distinct cellular processes involved in the function of the proteostasis network. Here we discuss main findings relating to the induction of neurodegeneration by C9ORF72 mutation and proteostasis deregulation, highlighting the role of the endoplasmic reticulum stress, nuclear transport, and autophagy in the disease process. We further discuss possible points of intervention to target proteostasis mediators to treat C9ORF72-linked ALS/FTD.

Background Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an emergent disease that threatens patients with texturized breast implants. Major concerns about the safety of these implants are leading to global changes to restrict the utilization of this product. The principal alternative is to perform breast augmentation utilizing smooth implants, given the lack of association with BIA-ALCL. The implications and costs of this intervention are unknown. Objectives The authors of this study determined the cost-effectiveness of smooth implants compared with texturized implants for breast augmentation surgery. Methods A tree decision model was utilized to analyze the cost-effectiveness. Model input parameters were derived from published sources. The capsular contracture (CC) rate was calculated from a meta-analysis. Effectiveness measures were life years, avoided BIA-ALCL, avoided deaths, and avoided reoperations. A sensitivity analysis was performed to test the robustness of the model. Results For avoided BIA-ALCL, the incremental cost was $18,562,003 for smooth implants over texturized implants. The incremental cost-effectiveness ratio was negative for life years, and avoided death and avoided reoperations were negative. The sensitivity analysis revealed that to avoid 1 case of BIA-ALCL, the utilization of smooth implants would be cost-effective for a risk of developing BIA-ALCL equal to or greater than 1:196, and there is a probability of CC with smooth implants equal to or less than 0.096. Conclusions The utilization of smooth implants to prevent BIA-ALCL is not cost-effective. Banning texturized implants to prevent BIA-ALCL may involve additional consequences, which should be considered in light of higher CC rates and more reoperations associated with smooth implants than with texturized implants.

Brain ageing is the main risk factor to develop dementia and neurodegenerative diseases, associated with a decay in the buffering capacity of the proteostasis network. We investigated the significance of the unfolded protein response (UPR), a major signaling pathway to cope with ER stress, to the functional deterioration of the brain during aging. Genetic disruption of the ER stress sensor IRE1α accelerated cognitive and motor decline during ageing. Exogenous bolstering of the UPR by overexpressing an active form of the UPR transcription factor XBP1 restored synaptic and cognitive function, in addition to reducing cell senescence. Proteomic profiling of hippocampal tissue indicated that XBP1s expression attenuated age-related alterations to synaptic function and pathways linked to neurodegenerative diseases. Overall, our results demonstrate that strategies to manipulate the UPR in mammals may sustain healthy brain ageing.

Aging is the major risk factor for the development of dementia and neurodegenerative disorders, and the aging brain manifests severe deficits in buffering capacity by the proteostasis network. Accordingly, we investigated the significance of the unfolded protein response (UPR), a major signaling pathway that copes with endoplasmic reticulum (ER) stress, to normal mammalian brain aging. Genetic disruption of ER stress sensor IRE1α accelerated cognitive and motor dysfunction during aging. Exogenous bolstering of the UPR by overexpressing an active form of the transcription factor XBP1 restored synaptic and cognitive function in addition to reducing cell senescence. Remarkably, proteomic profiling of hippocampal tissue indicated that XBP1s expression corrected age-related alterations in synaptic function. Collectively, our data demonstrate that strategies to manipulate the UPR sustain healthy brain aging.One Sentence SummaryThe IRE1/XBP1 pathway dictates when and how brain function declines during aging.

Made available in DSpace on 2018-12-11T17:21:03Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-08-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Universidade de São Paulo Brominated flame retardants are used in consumer goods to increase product resistance to fire and/or high temperatures. Polybrominated diphenyl ethers (PBDEs) are the most commonly employed class of brominated flame retardants because they are inexpensive and can effectively prevent flame from spreading. PBDEs are persistent, can bioaccumulate, are transported over long distances, and display toxicity. However, their toxic mechanisms of action have not been well established. Because mitochondria are recognized as the main energy-producing cell organelle and play a vital role in cellular function maintenance, here we apply mitochondria as an experimental model to evaluate the toxic effects of the PBDE congener BDE-153 (Hexa-BDE) at concentrations ranging from 0.1 to 25 μM. We also assess BDE-153 cytotoxicity to HepG2 cells in order to elucidate its mechanisms of toxicity. Exposure to BDE-153 affects isolated mitochondria: this congener can interact with the mitochondrial membrane, to dissipate the membrane potential and to induce significant ATP depletion. Furthermore, BDE-153 can diminish MTT reduction and cell proliferation and can interfere in cell cycle, as evaluated in cell cultures. These cytotoxic effects are related to mitochondrial dysfunction due to mitochondrial membrane potential dissipation and reactive oxygen species accumulation. These effects result in apoptotic cell death, as demonstrated by phosphatidylserine maintenance on the cell membrane external surface, nuclear condensation and fragmentation, and presence of pro-apoptotic factors such as cytochrome c and Apoptosis-inducing Factor (AIF) plus caspase 3 activation in the cytosol. Together, our results show PBDEs can induce cytotoxicity, reinforcing the idea that these compounds pose a risk to the exposed population. Department of Clinical Toxicological and Bromatological Analysis Faculty of Pharmaceutical Sciences of Ribeirão Preto University of São Paulo Department of Bioprocesses and Biotechnology Faculty of Agronomic Sciences of Botucatu São Paulo State University Department of Pathology São Paulo State University Botucatu Medical School Center for the Evaluation of the Environmental Impact on Human Health (TOXICAM) Departamento de Química Faculdade de Filosofia Ciências e Letras de Ribeirão Preto Universidade de São Paulo Department of Life Sciences University of Coimbra and Center for Neurosciences and Cell Biology University of Coimbra National Institute for Alternative Technologies of Detection Toxicological Evaluation and Removal of Micropollutants and Radioactives (INCT-DATREM) Unesp Institute of Chemistry, P.O. Box 355 Department of Bioprocesses and Biotechnology Faculty of Agronomic Sciences of Botucatu São Paulo State University Department of Pathology São Paulo State University Botucatu Medical School Center for the Evaluation of the Environmental Impact on Human Health (TOXICAM) National Institute for Alternative Technologies of Detection Toxicological Evaluation and Removal of Micropollutants and Radioactives (INCT-DATREM) Unesp Institute of Chemistry, P.O. Box 355 CAPES: PVE-A018/2012

Summary Perturbed neuronal proteostasis is a salient feature shared by both aging and protein misfolding disorders. The proteostasis network controls the health of the proteome by integrating pathways involved in protein synthesis, folding, trafficking, secretion, and their degradation. A reduction in the buffering capacity of the proteostasis network during aging may increase the risk to undergo neurodegeneration by enhancing the accumulation of misfolded proteins. As almost one‐third of the proteome is synthetized at the endoplasmic reticulum (ER), maintenance of its proper function is fundamental to sustain neuronal function. In fact, ER stress is a common feature of most neurodegenerative diseases. The unfolded protein response (UPR) operates as central player to maintain ER homeostasis or the induction of cell death of chronically damaged cells. Here, we discuss recent evidence placing ER stress as a driver of brain aging, and the emerging impact of neuronal UPR in controlling global proteostasis at the whole organismal level. Finally, we discuss possible therapeutic interventions to improve proteostasis and prevent pathological brain aging.

The conception that protein aggregates composed by misfolded proteins underlies the occurrence of several neurodegenerative diseases suggests that this phenomenon may have a common origin, ultimately driven by disruption of proteostasis control. The unfolded protein response (UPR) embodies a major element of the proteostasis network, which is engaged by endoplasmic reticulum (ER) stress. Chronic ER stress may operate as a possible mechanism of neurodegeneration, contributing to synaptic alterations, neuroinflammation and neuronal loss. In this review we discuss most recent findings relating ER stress and the development of distinct neurodegenerative diseases, and the possible strategies for disease intervention.

The life expectancy in the world's population is increasing, highlighting the need of better understanding of the cellular and molecular pathways that drive the aging process. Because aging is the major risk factor to develop neurodegenerative conditions such as Alzheimer's and Parkinson's disease, the number of patients affected is constantly increasing, representing a major social and economic problem. Importantly, abnormal protein aggregation is a transversal pathological event of most aging-related brain diseases, suggesting that the ability of neurons to handle alterations in the proteome is specifically altered (Kaushik and Cuervo, 2015). Several hallmarks of aging have been identified at the cellular and molecular level (Lopez-Otin et al., 2013; Kennedy et al., 2014), highlighting alterations in protein homeostasis or proteostasis. In fact, studies in simple model organisms indicate that the buffering capacity of the proteostasis network (PN) is reduced during aging (Douglas and Dillin, 2010; Mardones et al., 2015). The PN can be decomposed in different interrelated sub-networks including mechanisms responsible for protein synthesis, translation, folding, trafficking, quality control, secretion, and degradation (Balch et al., 2008). Sustained dysfunction of one or more components of the PN may translate into cell dysfunction and even proteotoxicity (Figure ​(Figure11). Figure 1 Global proteostasis network impairment during aging. Aging is the main risk factor to develop most neurodegenerative conditions and new evidence has pointed out to a progressive decline in the buffering capacity of the proteostasis network (PN) to handle ... Around 30% of the total proteome is synthetized at the endoplasmic reticulum (ER), an essential compartment involved in calcium handling, lipid synthesis among other functions. Different physiological and pathological stimuli can alter the function of this organelle, resulting in the accumulation of misfolded proteins. Importantly ER stress has been proposed as a central driver of several neurodegenerative conditions (Hetz and Mollereau, 2014). ER stress triggers the activation of the unfolded protein response (UPR), a central homeostatic pathway that orchestrates cells adaptation (Hetz et al., 2015). Studies in Caenorhabditis elegans and rats indicate that the activity of the UPR is drastically ablated during aging (Paz Gavilan et al., 2006; Naidoo et al., 2008; Ben-Zvi et al., 2009; Gavilan et al., 2009; Taylor and Dillin, 2013). The UPR is mediated by three main stress sensors located at the ER membrane including ATF6, PERK, and IRE1 (Ron and Walter, 2007). In brief, activation of IRE1 controls to the expression of the transcription factor XBP1s, leading to the upregulation of genes related with protein quality control, folding, ERAD, among other targets (Hetz et al., 2015). PERK phosphorylates eIF2α; inhibiting the translation of proteins into the ER, in addition to induce the expression of the transcription factor ATF4 regulating genes involved in the antioxidant response, amino acid metabolism and folding. Under irreversible ER stress ATF4 is essential to trigger apoptosis. ATF6 encodes a transcription factor in its cytosolic domain that upon processing is realized to control gene expression. Altogether, the activation of the UPR enforces adaptive mechanisms to sustain proteostasis or trigger cell demise when protein misfolding cannot be mitigated determining cell fate. Several studies in model organisms have uncovered the significance of UPR signaling to the aging process. IRE1 is the only ER stress sensor expressed in yeast and contributes to lifespan extension (Labunskyy et al., 2014), consistent with the fact that UPR activation in this organism is a relevant feature involved in the health span control triggered by caloric restriction (Choi et al., 2013). Similarly, genetic modifications that enhance the activity of the UPR improve replicative lifespan in Saccharomyces cerevisiae (Cui et al., 2015). Studies in C. elegans demonstrated that ablating the expression of XBP1 reduces life expectancy, associated with altered FOXO and insulin/IGF-1 signaling, a canonical aging pathway (Henis-Korenblit et al., 2010). Importantly, another report indicated that the ectopic expression of XBP1s in neurons has a significant effect in increasing lifespan in C. elegans (around 30%), representing one of the strongest aging modulator described so far in this specie (Taylor and Dillin, 2013). In D. melanogaster, the occurrence of ER stress and chronic inflammation alters the stem cell pool in the gut, affecting intestinal homeostasis during aging (Wang et al., 2014). Unexpectedly, a recent study indicated that chronic PERK signaling limits lifespan by controlling intestinal homeostasis, having important consequences to organismal health (Wang et al., 2015). In mammals, it was reported that the capacity to response to ER stress and activate IRE1 is attenuated in macrophages during aging, increasing the susceptibility to apoptosis (Song et al., 2013). Accordantly, aged rats present more pro-apoptotic UPR components as opposed to adaptive mediators such as BIP, calnexin, and PDI after ER stress induction (Paz Gavilan et al., 2006; Naidoo et al., 2008). In contrast, during the aging process B cells, osteoclasts, adipocyte tissue, the retina, and muscle experience elevated levels of ER stress and UPR activation (Chalil et al., 2015; Ghosh et al., 2015; Lenox et al., 2015; Baehr et al., 2016; Kannan et al., 2016). These observations suggest that aging maybe associated with accumulative damage to the ER rather than an attenuation of UPR responses. However, the role of ER proteostasis impartment in mammalian aging needs to be functionally defined. The UPR is emerging as a key player in the integration of systemic responses to handle proteostasis alterations at the whole organism, governed by the central nervous system (Sun et al., 2012; Taylor and Dillin, 2013). In addition to regulate the intrinsic capacity of the cell to respond to ER stress, activation of IRE1 in neurons engages an organismal reaction to promote stress resistance and longevity on a cell-nonautonomous manner (Taylor and Dillin, 2013). Interestingly, the activation of XBP1s in neurons per se was irrelevant to sustain organismal homeostasis, suggesting that the nervous system operates as a global adjustor of proteostasis, where the effectors in terms of enforcing aging resistance operate in the periphery, highlighting the intestine. Importantly, other studies have shown a similar mode of control for the heat shock response and the innate immunity in C. elegans (reviewed in Mardones et al., 2015). Similarly, in flies activation of PERK engages cell-nonautonomous responses in the gut during aging (Wang et al., 2015). The concept cell-nonautonomous UPR was recently validated in mammals, where the expression of XBP1s in the hypothalamus propagates signals to the periphery (i.e., the liver) to adjust energy metabolism (Williams et al., 2014). However, the specific mechanism of proteostasis control in mammals and the neuronal circuits mediating the propagation of UPR signals between cells remain to be determined. Importantly, in C. elegans the propagation of ER stress signals to the periphery depends on neurotransmitters, suggesting that signaling mechanisms may mediate the activation of UPR-like responses in the targeted tissue probably on a stress-independent manner (Taylor and Dillin, 2013). In this line, we recently reported that XBP1s has a novel function in controlling synaptic plasticity and behavior in mammals, where growth factors like BDNF can engage the pathway (Martinez et al., 2016). Although several studies are placing the ER PN as a relevant adjustor of organismal aging in several species, its actual impact to human aging remains to be established. Many important questions need to be solved in this emerging field: Why is the UPR buffering capacity attenuated during aging? How does the nervous system control organismal proteostasis? Is there a connection between ER stress and aging in protein misfolding disorders affecting the nervous system? Can we exploit the control of cell-nonautonomous UPR as a therapeutic strategy to delay aging? Importantly, recent studies suggest that oxidative damage could directly modify UPR stress sensors, ablating adaptive responses (Nakato et al., 2015). In addition, the redox status of the ER is altered during aging in C. elegans, suggesting that intrinsic physiological alterations to this subcellular compartment may underlay the reduced capacity of the pathway to handle proteostasis alterations when cells get old (Kirstein et al., 2015). Several novel drugs are available to fine-tune the UPR and reduce ER stress levels (Hetz et al., 2013), which promises new avenues to intervene brain aging which may reduce the risk to develop neurodegenerative diseases, improving health span.

Brain ischemia is a major cause of adult disability and death, and it represents a worldwide health problem with significant economic burden for modern society. The identification of the molecular pathways activated after brain ischemia, together with efficient technologies of gene delivery to the CNS, may lead to novel treatments based on gene therapy. Recombinant adeno-associated virus (rAAV) is an effective platform for gene transfer to the CNS. Here, we used a serotype 8 rAAV bearing the Y733F mutation (rAAV8-733) to overexpress co-chaperone E3 ligase CHIP (also known as Stub-1) in rat hippocampal neurons, both in an oxygen and glucose deprivation model in vitro and in a four-vessel occlusion model of ischemia in vivo. We show that CHIP overexpression prevented neuronal degeneration in both cases and led to a decrease of both eIF2α (serine 51) and AKT (serine 473) phosphorylation, as well as reduced amounts of ubiquitinated proteins following hypoxia or ischemia. These data add to current knowledge of ischemia-related signaling in the brain and suggest that gene therapy based on the role of CHIP in proteostasis may provide a new venue for brain ischemia treatment.

During a critical period, unilateral retinal lesions induce rapid axonal sprouting of intact axons into denervated territories within the collicular visual layers. We investigated the effect of caffeine, a non-selective A 1 and A 2a antagonist, upon the lesion-induced plasticity of retinotectal axons. Pigmented rats submitted to a temporal retinal lesion received either caffeine (30 mg/kg, ip) or saline treatment. The anterograde tracing revealed that caffeine treatment during the critical period resulted in a clear reduction on the sprouting of ipsilateral fibers but to an amplification of the plasticity after PND21, thus revealing opposite effects depending on the developmental time window.

Endoplasmic reticulum (ER) stress and protein misfolding are associated with various neurodegenerative diseases. ER stress activates Unfolded Protein Response (UPR), an adaptative response. However, severe ER stress can induce cell death. Here we show that the E3 ubiquitin ligase and co-chaperone Carboxyl Terminus HSP70/90 Interacting Protein (CHIP) prevents neuron death in the hippocampus induced by severe ER stress. Organotypic hippocampal slice cultures (OHSCs) were exposed to Tunicamycin, a pharmacological ER stress inducer, to trigger cell death. Overexpression of CHIP was achieved with a recombinant adeno-associated viral vector (rAAV) and significantly diminished ER stress-induced cell death, as shown by analysis of propidium iodide (PI) uptake, condensed chromatin, TUNEL and cleaved caspase 3 in the CA1 region of OHSCs. In addition, overexpression of CHIP prevented upregulation of both CHOP and p53 both pro-apoptotic pathways induced by ER stress. We also detected an attenuation of eIF2a phosphorylation promoted by ER stress. However, CHIP did not prevent upregulation of BiP/GRP78 induced by UPR. These data indicate that overexpression of CHIP attenuates ER-stress death response while maintain ER stress adaptative response in the central nervous system. These results indicate a neuroprotective role for CHIP upon UPR signalling. CHIP emerge as a candidate for clinical intervention in neurodegenerative diseases associated with ER stress.

It has been long known that somatosensory deafferentation can produce a dramatic reorganization of the somatotopic map, characterized by the retraction of the deafferented body part representation followed by expansion of unaffected body part representations (Pons et al., 1991). Mechanisms driving this phenomenon are not clear, nor is it evident whether they occur within the cortex and/or at subcortical structures (Florence et al., 1998; Jones and Pons, 1998; Jain et al., 2000). The occurrence of anatomical alterations in the cortex after deafferentation (Florence et al., 1998), in addition to the notion that neocortex is a very plastic structure, led to the view that cortical reorganization of sensory maps after lesions is driven, at least in part, by cortical mechanisms. Recent work published by Kambi et al. (2014) contradicts this paradigm. In order to determine the extent to which different sites of somatosensory pathway potentially contribute to cortical plasticity, Kambi and colleagues lesioned the dorsal column in monkeys. They then mapped the hand representation in area 3b during inactivation of the cortical face region or the cuneate nucleus. They showed that transient inactivation of normal chin representation in area 3b did not affect the expanded chin representation, even in the vicinity of the former face/hand boundary. Surprisingly, inactivation of the cuneate nucleus completely abolished responses of the expanded chin representation. These results suggest that after lesions of the dorsal column, reorganization in area 3b is dependent on plastic alterations in the brainstem, and not in the cortex. In fact, cortical reorganization was probably mediated by growth of trigeminal axons into the cuneate nucleus, as previously shown by Jain et al. (2000). The apparent absence of corticocortical mechanisms driving cortical receptive field reorganization in these experiments is very intriguing. Simultaneous recordings from the normal chin and deafferented body representation of S1 demonstrated the expansion of the chin area in animals with dorsal column lesions (Kambi et al., 2014). Based on previous studies, it would be expected that this was due to new corticocortical connections, at least in the vicinity of the face/hand border. Moreover, large-scale sprouting of cortical connections following forelimb deafferentation has already been shown by Florence et al. (1998). This divergence in the results might be related to the type of deafferentation. In Kambi et al. (2014), animals underwent a lesion in the dorsal column, which only interrupts the ascending somatosensory information from the forelimb. Unlike amputees or individuals that suffered complete sectioning of the spinal cord, they could still move their forelimb and consequently, the motor representation of the forelimb was still present. Accordingly, Kambi et al. (2011) has shown that the forelimb motor representation in M1 is substantially preserved after lesion of the dorsal column. Perhaps this is the key difference between models in which cortical mechanisms do or do not contribute to the reorganization of cortical maps. The hand representation in area 3b receives inputs from M1 (Liao et al., 2013). This direct feedback, as well as indirect inputs from other cortical areas, may be a potential source to keep cortical hand region activated during forelimb movements even after lesions of the dorsal column. In this scenario, maintenance of activity by area 3b cortical inputs would preclude production of signals that induce corticocortical sprouting, and so maintain the segregation between face and hand regions. This would explain why large-scale sprouting in area 3b was observed by Florence et al. (1998), but apparently not by Kambi et al. (2014). In that study, animals had amputations and at some point, they lost the motor representation of the missing body part. Accordingly, in humans that have suffered complete spinal cord injury, the reorganization of the somatosensory cortex also results from growth of new lateral connections in the cortex (Henderson et al., 2011). It is possible that depending on the type of deafferentation, the mechanisms driving the functional reorganization in the cortex can be called into action at different levels of the somatosensory system. It would be interesting to explore this question by using the same experimental protocol as Kambi et al. (2014) in amputee animals. Additionally, injections of neurotracers could be done into the deafferented cortical region in order to determine whether or not sprouting occurs after different types of deafferentation. Dendritic spine loss has also been described in deafferented cortical neurons after spinal cord injury (Ghosh et al., 2012). Previous work has shown that alterations in dendritic spine morphology occur after lesions in the central nervous system (Keck et al., 2013) and may differ depending on the site of reorganization and type of sensory deprivation (Whitt et al., 2014). Perhaps synaptic plasticity after lesions of the dorsal column, as performed by Kambi et al. (2014), may induce different cellular responses compared to other types of deafferentation. Additionally, the lack of signal in expanded chin representation after lidocaine infusion in cuneate, but not in area 3b raises the intriguing possibility that these two sites are independently regulated and may present different molecular features in response to lesions. Studies concerning such morphological alterations and the key molecular players behind them would shed light on the location and mechanisms of plastic changes after different types of lesion. Finally, differences in mechanism driving cortical reorganization after deafferentation may also correlate with manifestation of phantom limb pain. It has been proposed that this phenomenon is caused by a maladaptive plasticity in the somatosensory cortex (Ramachandran, 1993). Nevertheless, the occurrence of cortical sprouting, as well as nuances in synaptic plasticity after different types of deafferentation, may account for the development of phantom pain. If so, different types of deafferentation may demand different strategies for treatment. Interestingly, phantom pain is especially common in amputees. Perhaps this is due to specific cortical mechanisms (e.g., cortical sprouting) that are absent in other types of lesion (e.g., lesion of the dorsal column). A better understanding of the differences in mechanisms driving cortical reorganization between different types of deafferentation may provide valuable data for developing therapies to alleviate phantom limb pain.