Young Investigators Talks

Wednesday 7

Wed-YIT-1

Chair:
Graciela Mazzone

Anahi Bignante

INIMEC-CONICET-UNC

Aβ promotes amyloidogenic processing of APP through a Go/βγ signaling.

BACE1 cleavage on amyloid precursor protein (APP), is rate-limiting on Aβ biosynthesis. Some in vitro studies have demonstrated that exogenous Aβ triggers its own production by a mechanism which are unclear. Our previous findings suggest that APP acts as a pathologic receptor of Aβ, able to provoke neurodegeneration through Go/βγ intracellular signaling. In this work, we evaluated the role of APP/Go/βγ signaling, induced by aggregates of Aβ, promoting the encounter and interaction of APP with BACE1. Using quantitative colocalization, we found that fibrillar Aβ (fAβ) provoked an increase in the localization of APP and BACE1 in recycling endosomes (RE). Employing mutant forms of APP, we verified that this event is dependent of the interaction of APP with fAβ and with Go intracellular. Likewise, pharmacological inhibition of βγ with gallein, abrogated the Aβ-dependent convergence of endogenous APP and BACE1 in hippocampal neurons. Using Bimolecular Fluorescence Complementation (BiFC) technique in human neurons derivate from IPSCs, we found that fAβ and oligomeric Aβ (oAβ) were able to increment the APP/BACE1 interaction in RE; effect that was avoided by gallein. Finally, we correlated changes in APP and BACE1 interaction with changes in β-processing of APP by WB. Collectively, these findings uncover a feed-forward mechanism of amyloidogenesis that might contribute to amyloid pathology in early stages of Alzheimer’s disease and suggest that gallein might have clinical relevance

Mariana Holubiec

Instituto de Biología Celular y Neurociencia "Profesor Eduardo De Robertis" IBCN (UBA-CONICET)

Oxidative distress in Alzheimer Disease human organoids

While highly polarized neurons deal with physiological changes in local levels of reactive oxygen species (ROS), it is known that in early stages of Alzheimer disease (AD) imbalances in the management of ROS occur, promoting abnormal macromolecules oxidation. To test the association of increased oxidation and intracellular dynamic defects in the progression of AD we developed human brain organoids from iPSC control and APP Swedish mutation (APPSwe). We characterized organoid cell composition and AD pathological hallmarks, such as amyloid-like deposits stained with antibodies and classical Congo-red. Furthermore, we observed, in APPSwe organoids, an increase in Aβ reactive area as well as a decrease in full length APP levels by western blot and immunostaining. In addition, we developed a technique for microinjecting organoids with viral vectors or probes to measure mitochondrial dynamics and morphology, superoxide anion levels and reactive oxygen species. We found a significant increase of superoxide anion levels in live imaging of APPSwe organoids. We also described an increase in Glutaredoxin-2 reactive area and integrated intensity, suggesting changes in thiol-based regulation in AD. Our results highlight the relevance of modeling neurological diseases using complex tissue arrangements, and points to a clear impairment in oxidative stress pathways that, if modulated, could be used as a therapeutic strategy for treatment of abnormal oxidation in AD.

María Eugenia Pallarés

1-“Laboratorio de Programación Perinatal del Neurodesarrollo”. Instituto de Biología Celular y Neurociencias “Prof. E. de Robertis” (IBCN)- Facultad de Medicina, Universidad de Buenos Aires; 2-“Laboratorio de Neurobiología del Estrés”. Instituto de Investigaciones Biotecnológicas (IIB). UNSAM. CONICET.

“Early life stress and the programing of stress-coping abilities in juvenile rats”

Prenatal stress (PS) predisposes individuals to develop emotional disorders in later life, including depression and anxiety, which might be mediated by dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis response. However, to date, little studies have examined the effects of PS on stress coping abilities of younger individuals and it relevance for the early onset of stress-related disorders. In here we assessed the impact of PS on the emergence of anxiety-/depressive- like behaviors and HPA response to an acute stress in juvenile rats. We explored possible underlying molecular bases by changes in candidate stress-related genes and DNA-methylation levels in the hippocampus, a key structure in stress regulation. Also, we tested patterns of maternal behavior within early lactation. Stress during pregnancy enhanced pup-directed behavior of stressed dams. In the offspring, PS rats had enhanced stress-coping abilities than non-prenatally stressed rats. In the hippocampus, PS increased the expression of bdnf-IV and crhr1 although several sex differences changes on glucocorticoids and on BDNF receptors expressions were found. PS changes the hippocampal epigenetic landscape only in male offspring. Our results show that PS and maternal behavior induce dynamic alterations in the offspring that should be adaptive at younger ages, but potentially maladaptive in later life, highlighting the importance of including an ontogenetic approach when assessing the effects of PS.

Wed-YIT-2

Chair:
Verónica de la Fuente

Francisco Tomás Gallo

Laboratorio de Memoria y Cognición Molecular, Instituto de Neurociencia Cognitiva y Traslacional (CONICET - Fundación INECO - Universidad Favaloro. Laboratorio de Sueño y Memoria, Instituto Tecnológico de Buenos Aires (ITBA).

Dopamine modulates adaptive forgetting in medial prefrontal cortex

There are several ideas about the mechanisms of forgetting; some indicate that it is an active process that could be non-specific, but also dependent on the content depending on how it occurs. This study explores an active and selective forgetting mechanism whose function is to optimize the use and evocation of stored information. Anderson (1) developed a procedure in humans that he called “Evocation Practice Paradigm” in which an effect of “Retrieval-Induced Forgetting” is evidenced and it is postulated that it occurs by an executive control mechanism. Activation of the frontal areas during practice may indicate that forgetting of unpracticed items occurs by a mechanism of inhibitory control over medial temporal lobe (MTL) structures, of which there is extensive literature in humans. In our laboratory, a retrieval-induced forgetting paradigm for rodents was successfully developed (2). Using this paradigm, we show results in accordance with the alignments and hypotheses in humans. There is evidence of a dopaminergic role in PFC to solve tasks that require working memory or cognitive flexibility. We examined the effect of D1 receptor (D1R) blockade on mPFC during evocation. We observed that the activity of the ventral tegmental area (VTA) is necessary for the retrieval-induced forgetting but that this effect can be restored with the infusion of D1R agonists in the mPFC. We observed, using agonists and antagonists, a modulating effect of dopamine in the mPFC on retrieval-induce

Pamela Lopes da Cunha

Instituto de Biología Celular y Neurociencias “Pr. E. De Robertis”, CONICET. Facultad de Medicina. Universidad de Buenos Aires. Buenos Aires, Argentina. Centro de Neurociencias Cognitivas. Universidad de San Andres. Buenos Aires, Argentina

What we know of stress effects on memory: an integrative view through the behavioral tagging mechanism

The stress events influence a range of cognitive functions, including memory. However, its precise mechanisms are still unknown. Studying the interaction between acute stress event with different learning tasks, we found that stress can have both beneficial and detrimental effects on the consolidation of hippocampal-dependent memories. Our results support the Behavioral Tagging Hypothesis (BT) as a mechanism underlying the formation of long-term memories (LTM). According to this, some events could influence temporally associated memories by providing plasticity-related proteins (PRPs), necessary for the consolidation of the mnesic trace, or by competing for them. The BT also propose the association of these PRPs with a learning-induced neuronal tag, where proteins can be selectively used to maintain the plasticity that underlies memory. Experiments in rats showed that a weak training, which only induces short term memory, can be stabilized into LTM if an acute stress is experienced within a specific time window before or after learning. This promoting effect depends on protein synthesis induced by stress and the glucocorticoid receptors activation. However, if training is strong enough to generate LTM, a stress event impairs memory and our results support the competition for available proteins. Finally, we wondered if a similar phenomenon occurs in human memory. We also found a narrow time window for the stress modulation and learning-strength dependent effects.

Magdalena Pereyra

1 Universidad de Buenos Aires, Facultad de Medicina, Buenos Aires, Argentina, 2 CONICET-Universidad de Buenos Aires, Instituto de Biología Celular y Neurociencia "Dr. Eduardo De Robertis" (IBCN), Buenos Aires, Argentina.

AMPA receptor expression requirement during long-term memory retrieval and its association with mTORC1 signaling

Recently we reported that mechanistic/mammalian target of rapamycin complex 1 (mTORC1) activity during memory retrieval is required for long-term memories expression. Here we used inhibitory-avoidance task to evaluate the potential hippocampal mechanisms by which mTORC1 signaling participates in memory retrieval. First, we studied GluA-subunit trafficking during memory recall and its relationship with mTORC1 pathway. We found that pretest infusion of GluR23ɣ, a peptide that selectively blocks GluA2- containing AMPA receptor (AMPAR) endocytosis, prevented the amnesia induced by the inhibition of mTORC1 during retrieval. Additionally, we found that GluA1 levels decrease and GluA2 levels increase at the postsynaptic density subcellular fraction of rapamycin-infused animals during memory retrieval. Besides, GluA1 levels decreased at the synaptic plasma membrane fraction. Then, we evaluated the requirement of AMPAR subunit expression during retrieval. Infusion of GluA1 or GluA2 antisense oligonucleotides (ASO) before testing impaired memory retention. Memory impairment induced by GluA2 but not GluA1 ASO was reverted by GluA23ɣ infusion before testing. Our work indicates that de novo GluA1 and GluA2 AMPAR subunits expression is required for memory retrieval and suggests that mTORC1 might regulates AMPAR trafficking during retrieval. Our present results highlight the role of mTORC1 as a key determinant of memory retrieval that impacts the recruitment of different AMPAR subunits.

Wed-YIT-3

Chair:
Alejandra Pacchioni

Guillermina Canesini

Instituto de Salud y Ambiente del Litoral (ISAL), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral-CONICET, Santa Fe, Argentina.

Chronic exposure to a Glyphosate Based Herbicide alters the expression of key molecules involved in hypothalamic regulation of the rat oestrous cycle.

Glyphosate-based herbicides (GBHs) are extensively used and it has been reported that they may act as endocrine disruptors. Activation of steroid receptors in specific hypothalamic regions like the anteroventral periventricular nucleus (AvPv) and the arcuate nucleus (Arc) is necessary for ovulation and a normal oestrous cycle. This study aimed to describe the effects of chronic exposure to GBH during adult life, at levels close to the reference dose, on the hypothalamic regulation of the oestrous cycle. Adult rats were exposed for 3 months to 2 mg/kg/day of GBH through their diet (GBH Group-GG; Control Group-CG with saline solution). mRNA expression of Kisspeptin (Kiss) was evaluated in brain nuclei isolated by micropunch. GBH rats showed a lower percentage of time in proestrus-oestrous stages when compared to controls. Immunohistochemistry for oestrogen receptor alpha (ERα) and progesterone receptor (PR) showed changes in expression in AvPv, Arc and medial preoptic nuclei (Mpo) in rats exposed to GBH, the same as for REA and SMTR (ERα co-regulators). Kiss mRNA results showed significantly lower expression in the Mpo of the GG. These results suggest that a dose of GBH considered safe alters the rat´s cyclicity and modifies the expression of key brain molecules involved in its regulation. Therefore, these changes may provide new evidence of the possible effects of glyphosate on fertility at hypothalamic level.

Maria Paula Cornejo

IMBICE

The role of ghrelin receptor on the modulation of palatable food intake

Ghrelin is a hormone relevant in the context of eating disorders, as it promotes the consumption of palatable foods. Strikingly, ghrelin receptor, the growth hormone secretagogue receptor (GHSR), signals in the presence and in the absence (constitutive activity) of ghrelin. GHSR is expressed in the ventral tegmental area (VTA), a key nucleus of the mesolimbic pathway involved in processing rewarding experiences, such as the consumption of palatable foods. Ghrelin administration to humans activates reward-related brain nuclei, and intra-VTA administration of ghrelin in rodents increases, while GHSR blockage decreases, the intake of and the motivation for palatable foods. To understand the role of GHSR in the mesolimbic pathway and its regulation of high-fat (HF) food intake, we developed a binge-like eating protocol, in which mice are daily and time-limited exposed to a HF diet. We found that wild-type mice escalate HF diet intake over days and display an activation of the mesolimbic circuit, while GHSR-deficient mice eat less HF diet and show no activation of the mesolimbic pathway. We also found that blocking constitutive GHSR activity reduces HF diet intake in the binge-like eating protocol. Recently, we also showed that GHSR expression exclusively in dopamine neurons is sufficient to restore specific appetitive and consummatory behaviors towards HF diet. Thus, our studies show that GHSR in the mesolimbic pathway regulates reward-related behaviors towards HF diet.

Gimena Fernandez

Laboratorio de Neurofisiología. Instituto Multidisciplinario de Biología Celular (IMBICE) [CONICET -CIC-PBA -Universidad Nacional de La Plata (UNLP)], La Plata, Buenos Aires, Argentina.

Fasting induces remodeling of hypothalamic neuronal circuits controlling food intake and neuroendocrine axis in a growth hormone secretagogue receptor-dependent manner

The morphological and functional remodeling of neuronal circuits have been proposed to play a key role to ensure the control of the body homeostasis. Under energy-deficit states, the arcuate nucleus (ARC) neurons producing Agouti-related peptide (AgRP) and neuropeptide Y (NPY; ARCAgRP/NPY neurons) are activated and help to coordinate neuroendocrine and behavioral responses, including food intake, through projections to the hypothalamic paraventricular nucleus (PVH; ARC→PVH projections). Plasma ghrelin levels increase under energy-deficit states and activate ARCAgRP/NPY neurons by acting on the growth hormone secretagogue receptor (GHSR). Here, we hypothesized that activation of ARCAgRP/NPY neurons in fasted mice would promote morphological remodeling of the ARCAgRP/NPY→PVH projections in a GHSR-dependent manner, and such structural changes mediate the fasting-induced activation of the hypophysiotropic corticotrophin-releasing factor (CRF) producing neurons of the PVH. Using different experimental strategies we show that the connectivity between hypothalamic circuits controlling food intake and neuroendocrine responses can be remodeled in the adult brain, depending on the energy balance conditions, and that GHSR activity is a key regulator of this phenomenon.

Wed-YIT-4

Chairs:

Azul Silva

Lorena Rela

Santiago Boari

IFIBA-CONICET and DF, FCEN, UBA

Dynamical modeling and cortical oscillations in Serinus canaria song

Sensorimotor integration is a crucial aspect for encoding auditory representations of learned vocal behavior. Songbirds provide an excellent animal model to address this, since they are vocal learners and the neural circuits for song learning, production and perception are well understood. A dynamical model for the population activity in brain regions of this “song system” can reproduce characteristic air sac pressure patterns of canary song. For a cortical sensorimotor nucleus that presents similar activity patterns while singing and while perceiving the bird’s own song (BOS), the model predicts synchronized population activity at distinct temporal instances of song syllables. In this talk, I will discuss the neural model and its predictions. Also, I will report evidence of synchronous activity in response to auditory playbacks of the BOS. Extracellular recordings using 32-channel silicon probes allowed to study the local field potentials (LFP), single unit activity, and spatial synchronization. Rhythmic features of the song of canaries (Serinus canaria) allowed us to uncover neural oscillations locked to the behavior, which shows that predictions are compatible with experiments. Grouped data from different subjects share these features, suggesting a general strategy for neural coding. This program illustrates an example of the power that dynamical models provide to neuroscience research, in the form of testable hypotheses that drive -and feedback from- experiments.

Florencia Scarano

Center for Mind/Brain Sciences (CIMeC). University of Trento

Directional neurons selective for horizontal movement in a crab and their role in visually guided steering behaviour

Many animals rely mainly on vision to guide their behavior, for that they need to get information on the direction of moving objects, such as prey and predators. This can be achieved by direction selective neurons. Crabs offer several experimental advantages for studying some fundamental principles of neural processes involved in the directional component of behavioral responses. In these animals, the ability to pursue a moving prey requires fixing and tracking it with a region of the retina, which implies perceiving the directions in which the image deviates from the fixation point (Land & Layne, 1995). The neural mechanisms by which arthropods carry out these behaviors are unknown. Performing intracellular recordings in the lobula complex of the crab Neohelice granulata, we discovered neurons highly sensitive to direction that respond only to horizontal moving objects, thus reflecting an adaptation to the flat environment where they live. They respond with high frequency discharge of action potentials in the preferred direction, and with a sustained hyperpolarization in the null direction (Scarano et al, 2020). Furthermore, the collective activity of these neurons as an ensemble is suited to function as a deviator-detector system of targets moving away from the eye lateral pole. Based on this, we propose a role of these neurons for object tracking in crabs. These results provide a clear example of neuronal adaptation to salient features of a natural environment.
Thursday 8

Thu-YIT-5

Chair:
Juan Ferrario

Cecilia Tubert

Grupo de Neurociencia en Sistemas, IFIBIO Houssay - UBA - CONICET

Increased activity of D5R-Kv1.3 pathway in cholinergic interneurons contributes to the hypercholinergic state of parkinsonism and dyskinesias

Balanced actions of dopamine (DA) and acetylcholine (ACh) shape striatal function. Striatal cholinergic interneurons (ChIs) are the main striatal ACh source. In Parkinson´s disease (PD), DAergic nigrostriatal neurons degenerate, leading to a hypercholinergic state. L-dopa treatment can induce dyskinesias (LID). Previously, we found that ChIs are hyperexcitable in a mouse model of PD as result of a reduced Kv1.3 current, and, recently, that ChIs from LID mice are even more hyperexcitable. Our aim is to identify the mechanisms underlying this hyperexcitability, which are potential new therapeutic targets for Parkinson’s disease and dyskinesias. Because the D5R, which has constitutive (ligand-independent) activity, excites ChIs in physiological conditions, we hypothesize that an alteration of D5R signaling causes ChIs hyperexcitability in PD. With ex-vivo electrophysiological recordings, we found that D5R increases ChIs excitability by reducing a Kv1.3 current through a cAMP dependent signaling cascade. Moreover, in PD and LID mouse models, elevated levels of cAMP contribute to ChIs hyperexcitability. Finally, preliminary results suggest that this pathway is overactive due to an increased constitutive activation of D5R that entails an increased cAMP production followed by a reduction in Kv1.3 current, resulting in ChIs hyperexcitability.

Sung Min Yang

Harvard University

Neuron-class specific responses govern adaptive remodeling of myelination in the neocortex

Myelination plasticity plays a critical role in neurological function, including learning and memory. However, it is unknown whether this plasticity is enacted through uniform changes across all neuronal subtypes, or whether myelin dynamics vary between neuronal classes to enable fine-tuning of adaptive circuit responses. We performed in vivo two-photon imaging to investigate the dynamics of myelin sheaths along single axons of both excitatory callosal projection neurons (CPN) and inhibitory parvalbumin+ interneurons (PV-IN) in layer 2/3 of adult mouse visual cortex. We find that both neuron types show dynamic, homeostatic myelin remodeling under normal vision. However, monocular deprivation results in experience-dependent adaptive myelin remodeling only in PV-INs, but not in CPNs. Monocular deprivation induces an initial increase in elongation events in myelin segments of PV-INs, followed by a contraction phase affecting a separate cohort of segments. Sensory experience does not alter the generation rate of new myelinating oligodendrocytes, but can recruit pre-existing oligodendrocytes to generate new myelin sheaths. PV-INs also show a concomitant increase in axonal branch tip dynamics independent from myelination events. These findings demonstrate that distinct classes of neocortical neurons individualize adaptive remodeling of their myelination profiles to diversify circuit tuning in response to sensory experience.

Thu-YIT-6

Chair:
María Ana Contin

Leandro Casiraghi

University of Washington

Modulation of human sleep by the moon cycle

Environmental changes driven by the moon cycle are widely relevant in nature, but they are often unnoticed by humans. Lab studies have suggested potential effects of the moon cycle on sleep, but the detection of these in natural living conditions is challenged by modern life habits and ubiquitous access to electric light. To overcome this confound, we studied the sleep patterns of three Toba-Qom communities with different levels of access to electric light: a rural community with none, another with very limited access, and an urbanized community. Sleep timing showed a variation throughout the moon cycle, with delayed sleep times on nights preceding the full moon in the three populations. We hypothesized that this represents an adaptation to the hours of evening moonlight in the week before the full moon, which allow for extended evening activity. In fact, moonlight during the evening in the community with no electricity emulated the effects of the access to electric light on sleep that we previously reported in the Toba-Qom. Our results indicate that the availability of moonlight is a strong modulator of sleep and suggest that before access to artificially lit environments moonlight must have been an important driver of early night activity. The persistence of this modulation even in participants with full access to electric light suggests it could be driven by a different environmental cue other than moonlight, for example, changes in the gravitational pull of the moon.

Melisa Monteleone

Instituto de Investigaciones Biotecnológicas-UNSAM-CONICET

Potential use of the circulating neuronal glycoprotein M6a as a stress biomarker.

Depression affects hundreds of people. Despite its complex etiology, it is accepted that chronic stress is a key factor in its onset. Since stress main effects occur in the brain, an inaccessible area, we focused in detecting stress molecules in peripheral fluids such as blood or saliva. We showed that the neural glycoprotein M6a can be detected in serum. M6a contributes to neural plasticity promoting neurite and filopodium growth and synaptogenesis (Alfonso 2004, Brocco 2010, Formoso 2016). Next, we showed that M6a is carried in extracellular vesicles (EVs). EVs are liberated by cells in physiological and pathological conditions, can be isolated from almost all fluids and are used in the diagnosis of several diseases. Then, we showed that M6a-carrying EVs, but not EVs without M6a, induced a phenotypical change in COS-7 cells observed as filopodium formation. This indicates that M6a coupled to EVs might participate in cellular communication and contribute to cellular plasticity maintenance. Since M6a has also been related to several neuropsychiatric disorders, we studied serum M6a levels in chronically stressed animals. We found that stress altered M6a levels in blood. Thus, we proposed M6a as a putative stress biomarker (Monteleone, 2017). Now using patient saliva samples, we showed that M6a levels positively correlated with the scores for the perceived stress scale in individuals diagnosed with depression. This reinforces the idea of M6a as a stress-responsive protein

María Florencia Scaia

Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires.

Fighting fish: how the social decision making network and sex steroids can explain aggression.

The neural substrate of social behavior has been described as a “social decision-making network” (SDMN) in which each brain area is involved in multiple forms of social behavior, including aggression. Interestingly, the neuroendocrine basis of fighting behavior is understudied in females when compared to males. The aim of this study is to compare mechanisms regulating intrasexual aggression in male and female fish. In the first module, we studied the neural substrate of aggression in zebrafish. After performing dyadic encounters, behavioral data is clustered into two groups corresponding to both sexes. Network analysis shows a higher activation in all brain areas in animals exposed to social interaction, and suggests that patterns of brain activation in the SDMN in female winners differs from female losers and males. This suggests that differences in fighting behavior between males and female are related to differential pattern of brain activation in the SDMN. In the second module we studied the role of sex steroids on aggression in the cichlid Cichlasoma dimerus. Multivariate analysis including hormonal, morphometric and behavioral variables suggests that clustering of males and females into winners and losers is explained by specific agonistic displays, and that estradiol might have a role not only as a positive modulator of aggression, but also as a negative modulator of submission. This study highlights the importance of studying different species to study aggression.

Thu-YIT-7

Chair:
Marcela Brocco

Evelin Cotella

Pharmacology & Systems Physiology , University of Cincinnati

Prefrontal mechanism of resilience after adolescent chronic stress: Implications for dysregulation of fear responses in a model of posttraumatic stress disorder

Developmental stress is usually considered negative, although it is thought that mild to moderate stress during this period can sometimes promote adaptive responses, contributing to adult resilience. We first characterized the effects of chronic variable stress in adolescence (adol CVS) on behaviors related to corticolimbic functionality, to assess possible adult vulnerability and resilience to stress. Sprague Dawley rats were subjected to variable chronic stress in adolescence (adol CVS, 2 weeks, PND45). Adol CVS attenuated the impact of single prolonged stress (SPS), a robust model of PTSD on extinction and reinstatement in a fear conditioning paradigm. The analysis of Fos immunoreactivity pointed to the infralimbic cortex (IL) as a strong candidate for the mechanism behind the effect. We then studied the effect inhibition of IL activity during the experience of SPS by chemogenetics. This intervention enhanced the outcomes in a fear conditioning paradigm, pointing also to a possible involvement of the IL in mechanisms behind risk to PTSD after traumatic experiences. By electrophysiology, we observed that adol CVS is capable of preventing the reduction in excitability of the IL evoked by SPS. Our results indicated involvement of the IL in mediating effects related to resilience after adolescent stress and added new insights into the possible mechanisms behind developmentally driven interindividual differences in the vulnerability to disorders such as PTSD.

Santiago Cuesta

Universidad de Texas Southwestern Medical Center

When it comes to addiction, it might be better to listen to your gut

Substance use disorders (SUDs) affect millions of people worldwide. Yet, no successful evidence-based treatments have been developed. As with other mental health disorders, many factors contribute to SUD risk, including genetics, development, and environment. Recently, the gut-brain axis has emerged as a two-way street in host-microbial interactions. Gut microbiota composition and specific gut microbes modulate different social, stress-related, and cognitive behaviors and an altered gut microbiota has been associated with diverse neurological conditions, including SUDs. However, determining whether these microbiota changes cause, enhance, or are the consequence of psychiatric disease remains unclear. In this talk. I will focus on a) the mechanisms by which specific gut bacteria sense host signals that are altered with psychostimulant use, b) how gut bacteria respond to these host signals to establish themselves within the gut, and c) whether these changes in gut physiology affect the vulnerability to SUDs. Establishing a mechanistic understanding of the gut-brain axis will enable the development of new therapeutic strategies, including the identification of microbial targets that can be non-invasively exploited to reduce SUDs.

María Carolina Fabio

Instituto de Investigaciones Médicas Mercedes y Martín Ferreyra (INIMEC-CONICET-UNC). Facultad de Psicología UNC.

Transient Serotonin Inhibition during sensitive periods of development alters anxiety-related behavior and alcohol intake on adolescent mice.

Serotonin (5-HT) plays an important role in the organization of the central nervous system and in the development of psychiatric disorders, including anxiety, depression and addiction. Notably, disruption of the 5-HT system during sensitive periods of development exerts long term consequences, including altered anxiety response and problematic use of alcohol. We analyzed, in mice, the effects of transient 5-HT depletion at embryogenesis, infancy or adolescence on subsequent anxiety-like behavior, alcohol-induced anxiolysis and alcohol intake. We found that transient 5-HT inhibition during embryogenesis (gestational days 14-17; 200 mg/kg PCPA) induces compulsive-like behaviors and enhance ethanol-induced anxiolysis. We also injected PCPA at infancy (postnatal days 14-16; PD14-16) or adolescence (PD40-42). And found that female, but not male, mice transiently depleted of 5-HT at adolescence but not those depleted at the perinatal stage exhibited a significant reduction in anxiety response, which was accompanied by a significant reduction on alcohol intake. Transient 5-HT inhibition at prenatal stages may induce compulsive-like behaviors and make adolescents more vulnerable to anxiolytic effects of ethanol, making them more prone to consume higher amounts of alcohol. Nevertheless, when 5-HT system is interrupted during adolescence PCPA may selectively act as a protective factor for subsequent emergence of anxiety disorders and problematic use of alcohol.

Thu-YIT-8

Chair:
Nicolás Unsain

Maia Ludmila Budziñski

Instituto de Biomedicina de Buenos Aires-CONICET- Instituto Partner de la Sociedad Max Planck (IBioBA-CONICET-MPSP)

Sumoylation as a regulator of key proteins involved in the stress response

The hypothalamic-pituitary-adrenal (HPA) axis is critical for controlling the stress response. Glucocorticoids (GCs), downstream effectors of the axis, orchestrate the physiologic stress response and are also critical for restoring homeostasis via a negative feedback in various brain regions. Hyperactivity of the axis and increased levels of GCs in depressive patients have been ascribed to impaired feedback regulation, caused by altered function of the glucocorticoid receptor (GR). Antidepressants, in turn, ameliorate neurobiological disturbances in depression, including HPA axis hyperactivity, and alleviate depressive symptoms, which relate to restoring GR functions. FKBP51 is a key inhibitor of GR activity and its increased expression is linked to GR resistance, thus rendering FKBP51 an important therapeutic target. The activity of the GR is regulated by SUMO conjugation to FKBP51 and is necessary for FKBP51’s Hsp90-dependant inhibitory action on GR transcripcional regulation. We show that antidepressants inhibit FKBP51 SUMOylation by reducing PIAS4 E3 ligase and FKBP51 interaction. Also, that these drugs inhibit FKBP51 interaction with Hsp90 and therefore with GR, thus restoring GR activity. These effects are mainly due to the inhibition of FKBP51 SUMOylation. These results describe the action of antidepressants as modulators of FKBP51 SUMOylation as a molecular switch for restoring GR sensitivity, thereby providing new potential mechanisms of antidepressant intervention.

Martin Habif

Laboratory of Neuroplasticity and Neurotoxins (LAN&N). IBCN "Prof. EDUARDO DE ROBERTIS" Facultad de Medicina-UBA

Sexual dimorphism and cognitive impairment in a transgenic rat model of Alzheimer’s-like brain amyloidosis versus normal aging

McGill-R-Thy1-hAPP transgenic rat model (Tg) of Alzheimer´s Disease (AD) harbors the human APP with two familial AD mutations (Sw/Ind), which favor its amyloidogenic processing and Aβ accumulation. We recently reported LTM (previous reports only addressed STM) and social interaction deficits in 4 and 6-month-old (mo) hemizygous Tg males, while 4mo females seemed to learn and remember as wild type littermates (wt). To further characterize cognitive features in Tg rats and discriminate putative age deficits from those likely due to amyloidosis, we evaluated 12mo rats in a set of behavioral tasks. Both wt and Tg males and females equally habituated to the open field (OF). For the step-through inhibitory avoidance (IA) performance, whilst wt and Tg females formed LTM with memory persistence (after 14 days), wt males showed only LTM, and Tg neither of them. Wt rats of both sex showed STM and LTM for the novel object recognition (NOR) task, while Tg animals only showed STM. Unlike wt males, wt females were able to discriminate novel object location (NOL), but neither Tg females nor males could complete the task. Our results highlight sexual dimorphism in learning and the establishment of new associative memories in middle-aged rats. Also support potentially predictive features of the Tg model based on specific cognitive alterations, suggesting that similar changes might be present in preclinical AD phases, though unnoticed due to the neural and cognitive reserve of human beings.

Valentina Martinez Damonte

Stanford University

Cholecystokinin (CCK) modulates ventral tegmental area (VTA) GABAergic plasticity

The neural substrate of social behavior has been described as a “social decision-making network” (SDMN) in which each brain area is involved in multiple forms of social behavior, including aggression. Interestingly, the neuroendocrine basis of fighting behavior is understudied in females when compared to males. The aim of this study is to compare mechanisms regulating intrasexual aggression in male and female fish. In the first module, we studied the neural substrate of aggression in zebrafish. After performing dyadic encounters, behavioral data is clustered into two groups corresponding to both sexes. Network analysis shows a higher activation in all brain areas in animals exposed to social interaction, and suggests that patterns of brain activation in the SDMN in female winners differs from female losers and males. This suggests that differences in fighting behavior between males and female are related to differential pattern of brain activation in the SDMN. In the second module we studied the role of sex steroids on aggression in the cichlid Cichlasoma dimerus. Multivariate analysis including hormonal, morphometric and behavioral variables suggests that clustering of males and females into winners and losers is explained by specific agonistic displays, and that estradiol might have a role not only as a positive modulator of aggression, but also as a negative modulator of submission. This study highlights the importance of studying different species to study aggression.