123 results on '"Torres-Berrío A"'
Search Results
2. Oxycodone withdrawal induces HDAC1/HDAC2-dependent transcriptional maladaptations in the reward pathway in a mouse model of peripheral nerve injury
- Author
-
Pryce, Kerri D., Serafini, Randal A., Ramakrishnan, Aarthi, Nicolais, Andrew, Giosan, Ilinca M., Polizu, Claire, Torres-Berrío, Angélica, Vuppala, Sreeya, Kronman, Hope, Ruiz, Anne, Gaspari, Sevasti, Peña, Catherine J., Sakloth, Farhana, Mitsi, Vasiliki, van Duzer, John, Mazitschek, Ralph, Jarpe, Matthew, Shen, Li, Nestler, Eric J., and Zachariou, Venetia
- Published
- 2023
- Full Text
- View/download PDF
3. Author Correction: Oxycodone withdrawal induces HDAC1/HDAC2-dependent transcriptional maladaptations in the reward pathway in a mouse model of peripheral nerve injury
- Author
-
Pryce, Kerri D., Serafini, Randal A., Ramakrishnan, Aarthi, Nicolais, Andrew, Giosan, Ilinca M., Polizu, Claire, Torres-Berrío, Angélica, Vuppala, Sreeya, Kronman, Hope, Ruiz, Anne, Gaspari, Sevasti, Peña, Catherine J., Sakloth, Farhana, Mitsi, Vasiliki, van Duzer, John, Mazitschek, Ralph, Jarpe, Matthew, Shen, Li, Nestler, Eric J., and Zachariou, Venetia
- Published
- 2024
- Full Text
- View/download PDF
4. Blood miR-144-3p: a novel diagnostic and therapeutic tool for depression
- Author
-
van der Zee, Yentl Y., Eijssen, Lars M. T., Mews, Philipp, Ramakrishnan, Aarthi, Alvarez, Kelvin, Lardner, Casey K., Cates, Hannah M., Walker, Deena M., Torres-Berrío, Angélica, Browne, Caleb J., Cunningham, Ashley, Cathomas, Flurin, Kronman, Hope, Parise, Eric M., de Nijs, Laurence, Shen, Li, Murrough, James W., Rutten, Bart P. F., Nestler, Eric J., and Issler, Orna
- Published
- 2022
- Full Text
- View/download PDF
5. Crystallin Mu in Medial Amygdala Mediates the Effect of Social Experience on Cocaine Seeking in Males but Not in Females
- Author
-
Walker, Deena M., Zhou, Xianxiao, Cunningham, Ashley M., Ramakrishnan, Aarthi, Cates, Hannah M., Lardner, Casey K., Peña, Catherine J., Bagot, Rosemary C., Issler, Orna, Van der Zee, Yentl, Lipschultz, Andrew P., Godino, Arthur, Browne, Caleb J., Hodes, Georgia E., Parise, Eric M., Torres-Berrio, Angelica, Kennedy, Pamela J., Shen, Li, Zhang, Bin, and Nestler, Eric J.
- Published
- 2022
- Full Text
- View/download PDF
6. Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons
- Author
-
Kronman, Hope, Torres-Berrío, Angélica, Sidoli, Simone, Issler, Orna, Godino, Arthur, Ramakrishnan, Aarthi, Mews, Philipp, Lardner, Casey K., Parise, Eric M., Walker, Deena M., van der Zee, Yentl Y., Browne, Caleb J., Boyce, Brittany F., Neve, Rachael, Garcia, Benjamin A., Shen, Li, Peña, Catherine J., and Nestler, Eric J.
- Published
- 2021
- Full Text
- View/download PDF
7. Epigenetic Regulation of Neural Activity in the Depressed Brain: The Two Faces of the Histone Deacetylase SIRT1.
- Author
-
Torres-Berrío, Angélica
- Subjects
- *
HISTONE deacetylase , *SIRTUINS , *EPIGENETICS - Published
- 2024
- Full Text
- View/download PDF
8. MiR-218: a molecular switch and potential biomarker of susceptibility to stress
- Author
-
Torres-Berrío, Angélica, Nouel, Dominique, Cuesta, Santiago, Parise, Eric M., Restrepo-Lozano, José María, Larochelle, Pier, Nestler, Eric J., and Flores, Cecilia
- Published
- 2020
- Full Text
- View/download PDF
9. The opioid system in stress-induced memory disorders: From basic mechanisms to clinical implications in post-traumatic stress disorder and Alzheimer's disease
- Author
-
Torres-Berrio, Angélica and Nava-Mesa, Mauricio O.
- Published
- 2019
- Full Text
- View/download PDF
10. Dopamine Axon Targeting in the Nucleus Accumbens in Adolescence Requires Netrin-1
- Author
-
Santiago Cuesta, Dominique Nouel, Lauren M. Reynolds, Alice Morgunova, Angélica Torres-Berrío, Amanda White, Giovanni Hernandez, Helen M. Cooper, and Cecilia Flores
- Subjects
adolescence ,cortical development ,guidance cues ,nucleus accumbens ,dopamine innervation ,Biology (General) ,QH301-705.5 - Abstract
The fine arrangement of neuronal connectivity during development involves the coordinated action of guidance cues and their receptors. In adolescence, the dopamine circuitry is still developing, with mesolimbic dopamine axons undergoing target-recognition events in the nucleus accumbens (NAcc), while mesocortical projections continue to grow toward the prefrontal cortex (PFC) until adulthood. This segregation of mesolimbic versus mesocortical dopamine pathways is mediated by the guidance cue receptor DCC, which signals dopamine axons intended to innervate the NAcc to recognize this region as their final target. Whether DCC-dependent mesolimbic dopamine axon targeting in adolescence requires the action of its ligand, Netrin-1, is unknown. Here we combined shRNA strategies, quantitative analysis of pre- and post-synaptic markers of neuronal connectivity, and pharmacological manipulations to address this question. Similar to DCC levels in the ventral tegmental area, Netrin-1 expression in the NAcc is dynamic across postnatal life, transitioning from high to low expression across adolescence. Silencing Netrin-1 in the NAcc in adolescence results in an increase in the expanse of the dopamine input to the PFC in adulthood, with a corresponding increase in the number of presynaptic dopamine sites. This manipulation also results in altered dendritic spine density and morphology of medium spiny neurons in the NAcc in adulthood and in reduced sensitivity to the behavioral activating effects of the stimulant drug of abuse, amphetamine. These cellular and behavioral effects mirror those induced by Dcc haploinsufficiency within dopamine neurons in adolescence. Dopamine targeting in adolescence requires the complementary interaction between DCC receptors in mesolimbic dopamine axons and Netrin-1 in the NAcc. Factors regulating either DCC or Netrin-1 in adolescence can disrupt mesocorticolimbic dopamine development, rendering vulnerability or protection to phenotypes associated with psychiatric disorders.
- Published
- 2020
- Full Text
- View/download PDF
11. Author Correction: Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons
- Author
-
Kronman, Hope, Torres-Berrío, Angélica, Sidoli, Simone, Issler, Orna, Godino, Arthur, Ramakrishnan, Aarthi, Mews, Philipp, Lardner, Casey K., Parise, Eric M., Walker, Deena M., van der Zee, Yentl Y., Browne, Caleb J., Boyce, Brittany F., Neve, Rachael, Garcia, Benjamin A., Shen, Li, Peña, Catherine J., and Nestler, Eric J.
- Published
- 2021
- Full Text
- View/download PDF
12. Monomethylation of Lysine 27 at Histone 3 Confers Lifelong Susceptibility to Stress
- Author
-
Angélica Torres-Berrío, Molly Estill, Aarthi Ramakrishnan, Hope Kronman, Vishwendra Patel, Angélica Minier-Toribio, Orna Issler, Caleb J. Browne, Eric M. Parise, Yentl van der Zee, Deena Walker, Freddyson J. Martínez-Rivera, Casey K. Lardner, Romain Durand-de Cuttoli, Scott J. Russo, Li Shen, Simone Sidoli, and Eric J. Nestler
- Subjects
Article - Abstract
SUMMARYHistone post-translational modifications are critical for mediating persistent alterations in gene expression. By combining unbiased proteomics profiling, and genome-wide approaches, we uncovered a role for mono-methylation of lysine 27 at histone H3 (H3K27me1) in the enduring effects of stress. Specifically, mice exposed to early life stress (ELS) or to chronic social defeat stress (CSDS) in adulthood displayed increased enrichment of H3K27me1, and transient decreases in H3K27me2, in the nucleus accumbens (NAc), a key brain-reward region. Stress induction of H3K27me1 was mediated by the VEFS domain of SUZ12, a core subunit of the polycomb repressive complex-2, which is induced by chronic stress and controls H3K27 methylation patterns. Overexpression of the VEFS domain led to social, emotional, and cognitive abnormalities, and altered excitability of NAc D1 mediums spiny neurons. Together, we describe a novel function of H3K27me1 in brain and demonstrate its role as a “chromatin scar” that mediates lifelong stress susceptibility.
- Published
- 2023
13. Transcriptional signatures of heroin intake and seeking throughout the brain reward circuit
- Author
-
Browne, Caleb J, primary, Futamura, Rita, additional, Minier-Toribio, Angélica, additional, Hicks, Emily M, additional, Ramakrishnan, Aarthi, additional, Martínez-Rivera, Freddyson, additional, Estill, Molly, additional, Godino, Arthur, additional, Parise, Eric M, additional, Torres-Berrío, Angélica, additional, Cunningham, Ashley M, additional, Hamilton, Peter J, additional, Walker, Deena M, additional, Huckins, Laura M., additional, Hurd, Yasmin L, additional, Shen, Li, additional, and Nestler, Eric J, additional
- Published
- 2023
- Full Text
- View/download PDF
14. Transcriptional signatures of heroin intake and seeking throughout the brain reward circuit
- Author
-
Caleb J Browne, Rita Futamura, Angélica Minier-Toribio, Emily M Hicks, Aarthi Ramakrishnan, Freddyson Martínez-Rivera, Molly Estill, Arthur Godino, Eric M Parise, Angélica Torres-Berrío, Ashley M Cunningham, Peter J Hamilton, Deena M Walker, Laura M. Huckins, Yasmin L Hurd, Li Shen, and Eric J Nestler
- Abstract
Opioid use disorder (OUD) looms as one of the most severe medical crises currently facing society. More effective therapeutics for OUD requires in-depth understanding of molecular changes supporting drug-taking and relapse. Recent efforts have helped advance these aims, but studies have been limited in number and scope. Here, we develop a brain reward circuit-wide atlas of opioid-induced transcriptional regulation by combining RNA sequencing (RNAseq) and heroin self-administration in male mice modeling multiple OUD-relevant conditions: acute heroin exposure, chronic heroin intake, context-induced drug-seeking following prolonged abstinence, and heroin-primed drug-seeking (i.e., “relapse”). Bioinformatics analysis of this rich dataset identified numerous patterns of molecular changes, transcriptional regulation, brain-region-specific involvement in various aspects of OUD, and both region-specific and pan-circuit biological domains affected by heroin. Integrating RNAseq data with behavioral outcomes using factor analysis to generate an “addiction index” uncovered novel roles for particular brain regions in promoting addiction-relevant behavior, and implicated multi-regional changes in affected genes and biological processes. Comparisons with RNAseq and genome-wide association studies from humans with OUD reveal convergent molecular regulation that are implicated in drug-taking and relapse, and point to novel gene candidates with high therapeutic potential for OUD. These results outline broad molecular reprogramming that may directly promote the development and maintenance of OUD, and provide a foundational resource to the field for future research into OUD mechanisms and treatment strategies.
- Published
- 2023
15. The long noncoding RNA FEDORA is a cell type– and sex-specific regulator of depression
- Author
-
Issler, Orna, primary, van der Zee, Yentl Y., additional, Ramakrishnan, Aarthi, additional, Xia, Sunhui, additional, Zinsmaier, Alexander K., additional, Tan, Chunfeng, additional, Li, Wei, additional, Browne, Caleb J., additional, Walker, Deena M., additional, Salery, Marine, additional, Torres-Berrío, Angélica, additional, Futamura, Rita, additional, Duffy, Julia E., additional, Labonte, Benoit, additional, Girgenti, Matthew J., additional, Tamminga, Carol A., additional, Dupree, Jeffrey L., additional, Dong, Yan, additional, Murrough, James W., additional, Shen, Li, additional, and Nestler, Eric J., additional
- Published
- 2022
- Full Text
- View/download PDF
16. A Regional and Projection-Specific Role of RGSz1 in the Ventrolateral Periaqueductal Grey in the Modulation of Morphine Reward
- Author
-
Sakloth, Farhana, primary, Sanchez-Reyes, Omar B., additional, Ruiz, Anne, additional, Nicolais, Andrew, additional, Serafini, Randal A., additional, Pryce, Kerri D., additional, Bertherat, Feodora, additional, Torres-Berrío, Angélica, additional, Gomes, Ivone, additional, Devi, Lakshmi A., additional, Wacker, Daniel, additional, and Zachariou, Venetia, additional
- Published
- 2022
- Full Text
- View/download PDF
17. The long noncoding RNA FEDORA is a cell type- and sex-specific regulator of depression
- Author
-
Orna Issler, Yentl Y. van der Zee, Aarthi Ramakrishnan, Sunhui Xia, Alexander K. Zinsmaier, Chunfeng Tan, Wei Li, Caleb J. Browne, Deena M. Walker, Marine Salery, Angélica Torres-Berrío, Rita Futamura, Julia E. Duffy, Benoit Labonte, Matthew J. Girgenti, Carol A. Tamminga, Jeffrey L. Dupree, Yan Dong, James W. Murrough, Li Shen, and Eric J. Nestler
- Subjects
Multidisciplinary - Abstract
Women suffer from depression at twice the rate of men, but the underlying molecular mechanisms are poorly understood. Here, we identify marked baseline sex differences in the expression of long noncoding RNAs (lncRNAs), a class of regulatory transcripts, in human postmortem brain tissue that are profoundly lost in depression. One such human lncRNA, RP11-298D21.1 (which we termed FEDORA), is enriched in oligodendrocytes and neurons and up-regulated in the prefrontal cortex (PFC) of depressed females only. We found that virally expressing FEDORA selectively either in neurons or in oligodendrocytes of PFC promoted depression-like behavioral abnormalities in female mice only, changes associated with cell type–specific regulation of synaptic properties, myelin thickness, and gene expression. We also found that blood FEDORA levels have diagnostic implications for depressed women and are associated with clinical response to ketamine. These findings demonstrate the important role played by lncRNAs, and FEDORA in particular, in shaping the sex-specific landscape of the brain and contributing to sex differences in depression.
- Published
- 2022
18. Resilience to amphetamine in mouse models of netrin-1 haploinsufficiency: role of mesocortical dopamine
- Author
-
Pokinko, Matthew, Moquin, Luc, Torres-Berrío, Angélica, Gratton, Alain, and Flores, Cecilia
- Published
- 2015
- Full Text
- View/download PDF
19. Antidepressant actions of ketamine engage cell-specific translation via eIF4E
- Author
-
Angélica Torres-Berrío, Gareth M. Rurak, Mohammad J. Eslamizade, Natalina Salmaso, Danilo De Gregorio, Argel Aguilar-Valles, Agnieszka Skaleka, Martha Lopez-Canul, Nahum Sonenberg, Sara Bermudez, Jean-Claude Lacaille, Abdessattar Khlaifia, Gabriella Gobbi, Edna Matta-Camacho, Stephanie Simard, Aguilar-Valles, A., De Gregorio, D., Matta-Camacho, E., Eslamizade, M. J., Khlaifia, A., Skaleka, A., Lopez-Canul, M., Torres-Berrio, A., Bermudez, S., Rurak, G. M., Simard, S., Salmaso, N., Gobbi, G., Lacaille, J. -C., and Sonenberg, N.
- Subjects
0301 basic medicine ,Multidisciplinary ,business.industry ,Molecular neuroscience ,Pharmacology ,Hippocampal formation ,Neurotransmission ,Inhibitory postsynaptic potential ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Excitatory postsynaptic potential ,Medicine ,Antidepressant ,Ketamine ,business ,030217 neurology & neurosurgery ,medicine.drug ,Behavioural despair test - Abstract
Effective pharmacotherapy for major depressive disorder remains a major challenge, as more than 30% of patients are resistant to the first line of treatment (selective serotonin reuptake inhibitors)1. Sub-anaesthetic doses of ketamine, a non-competitive N-methyl-d-aspartate receptor antagonist2,3, provide rapid and long-lasting antidepressant effects in these patients4–6, but the molecular mechanism of these effects remains unclear7,8. Ketamine has been proposed to exert its antidepressant effects through its metabolite (2R,6R)-hydroxynorketamine ((2R,6R)-HNK)9. The antidepressant effects of ketamine and (2R,6R)-HNK in rodents require activation of the mTORC1 kinase10,11. mTORC1 controls various neuronal functions12, particularly through cap-dependent initiation of mRNA translation via the phosphorylation and inactivation of eukaryotic initiation factor 4E-binding proteins (4E-BPs)13. Here we show that 4E-BP1 and 4E-BP2 are key effectors of the antidepressant activity of ketamine and (2R,6R)-HNK, and that ketamine-induced hippocampal synaptic plasticity depends on 4E-BP2 and, to a lesser extent, 4E-BP1. It has been hypothesized that ketamine activates mTORC1–4E-BP signalling in pyramidal excitatory cells of the cortex8,14. To test this hypothesis, we studied the behavioural response to ketamine and (2R,6R)-HNK in mice lacking 4E-BPs in either excitatory or inhibitory neurons. The antidepressant activity of the drugs is mediated by 4E-BP2 in excitatory neurons, and 4E-BP1 and 4E-BP2 in inhibitory neurons. Notably, genetic deletion of 4E-BP2 in inhibitory neurons induced a reduction in baseline immobility in the forced swim test, mimicking an antidepressant effect. Deletion of 4E-BP2 specifically in inhibitory neurons also prevented the ketamine-induced increase in hippocampal excitatory neurotransmission, and this effect concurred with the inability of ketamine to induce a long-lasting decrease in inhibitory neurotransmission. Overall, our data show that 4E-BPs are central to the antidepressant activity of ketamine. The antidepressant-like effects of ketamine in mice depend on the expression of specific eIF4E-binding proteins in excitatory and inhibitory neurons.
- Published
- 2020
20. A Regional and Projection-Specific Role of RGSz1 in the Ventrolateral Periaqueductal Grey in the Modulation of Morphine Reward
- Author
-
Farhana Sakloth, Omar B. Sanchez-Reyes, Anne Ruiz, Andrew Nicolais, Randal A. Serafini, Kerri D. Pryce, Feodora Bertherat, Angélica Torres-Berrío, Ivone Gomes, Lakshmi A. Devi, Daniel Wacker, and Venetia Zachariou
- Subjects
Pharmacology ,Analgesics, Opioid ,Mice ,Morphine ,Reward ,GTP-Binding Proteins ,Receptors, Opioid, mu ,Molecular Medicine ,Animals ,Periaqueductal Gray ,Signal Transduction - Abstract
Opioid analgesics exert their therapeutic and adverse effects by activating
- Published
- 2022
21. Sex-Specific Role for SLIT1 in Regulating Stress Susceptibility
- Author
-
van der Zee, Yentl Y., primary, Lardner, Casey K., additional, Parise, Eric M., additional, Mews, Philipp, additional, Ramakrishnan, Aarthi, additional, Patel, Vishwendra, additional, Teague, Collin D., additional, Salery, Marine, additional, Walker, Deena M., additional, Browne, Caleb J., additional, Labonté, Benoit, additional, Parise, Lyonna F., additional, Kronman, Hope, additional, Penã, Catherine J., additional, Torres-Berrío, Angélica, additional, Duffy, Julia E., additional, de Nijs, Laurence, additional, Eijssen, Lars M.T., additional, Shen, Li, additional, Rutten, Bart, additional, Issler, Orna, additional, and Nestler, Eric J., additional
- Published
- 2022
- Full Text
- View/download PDF
22. Cooperative synaptic and intrinsic plasticity in a disynaptic limbic circuit drive stress-induced anhedonia and passive coping in mice
- Author
-
Carol A. Tamminga, Antonello Bonci, David J. Barker, Jocelyn Wu, Eric M. Parise, Leonardo Bontempi, Sissi Palma Ribeiro, Angélica Torres-Berrío, Alejandra Lopez, Marisela Morales, Marco Pignatelli, Hugo A. Tejeda, Mingshan Xue, Zhao-Lin Cai, Yocasta Alvarez-Bagnarol, Eric J. Nestler, Federica Lucantonio, and Rosa Anna Maria Marino
- Subjects
0301 basic medicine ,Anhedonia ,Lateral hypothalamus ,Physiology ,Hippocampus ,Nucleus accumbens ,Biology ,Medium spiny neuron ,Nucleus Accumbens ,Article ,Mice ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Adaptation, Psychological ,medicine ,Animals ,Molecular Biology ,Receptors, Dopamine D1 ,Mice, Inbred C57BL ,Psychiatry and Mental health ,030104 developmental biology ,Excitatory postsynaptic potential ,Brain stimulation reward ,medicine.symptom ,Depotentiation ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Stress promotes negative affective states, which include anhedonia and passive coping. While these features are in part mediated by neuroadaptations in brain reward circuitry, a comprehensive framework of how stress-induced negative affect may be encoded within key nodes of this circuit is lacking. Here, we show in a mouse model for stress-induced anhedonia and passive coping that these phenomena are associated with increased synaptic strength of ventral hippocampus (VH) excitatory synapses onto D1 medium spiny neurons (D1-MSNs) in the nucleus accumbens medial shell (NAcmSh), and with lateral hypothalamus (LH)-projecting D1-MSN hyperexcitability mediated by decreased inwardly rectifying potassium channel (IRK) function. Stress-induced negative affective states are prevented by depotentiation of VH to NAcmSh synapses, restoring Kir2.1 function in D1R-MSNs, or disrupting co-participation of these synaptic and intrinsic adaptations in D1-MSNs. In conclusion, our data provide strong evidence for a disynaptic pathway controlling maladaptive emotional behavior.
- Published
- 2020
23. Blood miR-144-3p: a novel diagnostic and therapeutic tool for depression
- Author
-
Yentl Y. van der Zee, Lars M. T. Eijssen, Philipp Mews, Aarthi Ramakrishnan, Kelvin Alvarez, Casey K. Lardner, Hannah M. Cates, Deena M. Walker, Angélica Torres-Berrío, Caleb J. Browne, Ashley Cunningham, Flurin Cathomas, Hope Kronman, Eric M. Parise, Laurence de Nijs, Li Shen, James W. Murrough, Bart P. F. Rutten, Eric J. Nestler, Orna Issler, RS: MHeNs - R3 - Neuroscience, Psychiatrie & Neuropsychologie, Basic Neuroscience 1, and MUMC+: MA Psychiatrie (3)
- Subjects
EXPRESSION ,Depressive Disorder, Major ,STRESS ,MICRORNA ,MAJOR DEPRESSION ,PERIPHERAL-BLOOD ,SUSCEPTIBILITY ,RESILIENCE ,CELL DISTRIBUTION WIDTH ,Antidepressive Agents ,Article ,Epigenesis, Genetic ,Cellular and Molecular Neuroscience ,Psychiatry and Mental health ,Mice ,MicroRNAs ,SOCIAL DEFEAT ,TARGET ,Animals ,Ketamine ,Molecular Biology ,Biomarkers - Abstract
Major depressive disorder (MDD) is the leading cause of disability worldwide. There is an urgent need for objective biomarkers to diagnose this highly heterogeneous syndrome, assign treatment, and evaluate treatment response and prognosis. MicroRNAs (miRNAs) are short non-coding RNAs, which are detected in body fluids that have emerged as potential biomarkers of many disease conditions. The present study explored the potential use of miRNAs as biomarkers for MDD and its treatment. We profiled the expression levels of circulating blood miRNAs from mice that were collected before and after exposure to chronic social defeat stress (CSDS), an extensively validated mouse model used to study depression, as well as after either repeated imipramine or single-dose ketamine treatment. We observed robust differences in blood miRNA signatures between stress-resilient and stress-susceptible mice after an incubation period, but not immediately after exposure to the stress. Furthermore, ketamine treatment was more effective than imipramine at re-establishing baseline miRNA expression levels, but only in mice that responded behaviorally to the drug. We identified the red blood cell-specific miR-144-3p as a candidate biomarker to aid depression diagnosis and predict ketamine treatment response in stress-susceptible mice and MDD patients. Lastly, we demonstrate that systemic knockdown of miR-144-3p, via subcutaneous administration of a specific antagomir, is sufficient to reduce the depression-related phenotype in stress-susceptible mice. RNA-sequencing analysis of blood after such miR-144-3p knockdown revealed a blunted transcriptional stress signature as well. These findings identify miR-144-3p as a novel target for diagnosis of MDD as well as for antidepressant treatment, and enhance our understanding of epigenetic processes associated with depression.
- Published
- 2021
24. A Regional and Projection-Specific Role of RGSz1 in the Ventrolateral Periaqueductal Grey in the Modulation of Morphine Reward
- Author
-
Sakloth, Farhana, Sanchez-Reyes, Omar B., Ruiz, Anne, Nicolais, Andrew, Serafini, Randal A., Pryce, Kerri D., Bertherat, Feodora, Torres-Berrío, Angélica, Gomes, Ivone, Devi, Lakshmi A., Wacker, Daniel, and Zachariou, Venetia
- Abstract
Opioid analgesics exert their therapeutic and adverse effects by activating μopioid receptors (MOPR); however, functional responses to MOPR activation are modulated by distinct signal transduction complexes within the brain. The ventrolateral periaqueductal gray (vlPAG) plays a critical role in modulation of nociception and analgesia, but the exact intracellular pathways associated with opioid responses in this region are not fully understood. We previously showed that knockout of the signal transduction modulator Regulator of G protein Signaling z1 (RGSz1) enhanced analgesic responses to opioids, whereas it decreased the rewarding efficacy of morphine. Here, we applied viral mediated gene transfer methodology and delivered adeno-associated virus (AAV) expressing Cre recombinase to the vlPAG of RGSz1fl\flmice to demonstrate that downregulation of RGSz1 in this region decreases sensitivity to morphine in the place preference paradigm, under pain-free as well as neuropathic pain states. We also used retrograde viral vectors along with flippase-dependent Cre vectors to conditionally downregulate RGSz1 in vlPAG projections to the ventral tegmental area (VTA) and show that downregulation of RGSz1 prevents the development of place conditioning to low morphine doses. Consistent with the role for RGSz1 as a negative modulator of MOPR activity, RGSz1KO enhances opioid-induced cAMP inhibition in periaqueductal gray (PAG) membranes. Furthermore, using a new generation of bioluminescence resonance energy transfer (BRET) sensors, we demonstrate that RGSz1 modulates Gαz but not other Gαi family subunits and selectively impedes MOPR-mediated Gαz signaling events invoked by morphine and other opioids. Our work highlights a regional and circuit-specific role of the G protein–signaling modulator RGSz1 in morphine reward, providing insights on midbrain intracellular pathways that control addiction-related behaviors.SIGNIFICANCE STATEMENTThis study used advanced genetic mouse models to highlight the role of the signal transduction modulator named RGSz1 in responses to clinically used opioid analgesics. We show that RGSz1 controls the rewarding efficacy of opioids by actions in ventrolateral periaqueductal gray projections to the ventral tegmental area, a key component of the midbrain dopamine pathway. These studies highlight novel mechanisms by which pain-modulating structures control the rewarding efficacy of opioids.
- Published
- 2023
- Full Text
- View/download PDF
25. The ventral hippocampus is required for behavioral flexibility but not for allocentric/egocentric learning
- Author
-
Angélica Torres-Berrío, Martha Lopez-Canul, and Viviana Vargas-López
- Subjects
Male ,0301 basic medicine ,Perseveration ,Prefrontal Cortex ,Hippocampus ,Context (language use) ,Tetrodotoxin ,Rats, Sprague-Dawley ,03 medical and health sciences ,Cognition ,0302 clinical medicine ,Spatial strategy ,medicine ,Animals ,Learning ,Latency (engineering) ,Maze Learning ,Social Behavior ,Prefrontal cortex ,Behavior, Animal ,General Neuroscience ,Flexibility (personality) ,Altruism ,Rats ,030104 developmental biology ,Egocentrism ,Space Perception ,medicine.symptom ,Psychology ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Behavioral flexibility is a complex cognitive function that allows for the rapid adaptation to a changing environment. This ability is modulated by the proper function of the prefrontal cortex (PFC), which receives important projections from the ventral hippocampus (vHPC). In this context, the vHPC might play a very important role in behavioral flexibility. Here, we infused the voltage-gated sodium channel blocker tetrodotoxin (TTX) to bilaterally inactivate the vHPC in adult rats and assessed behavioral flexibility in a spatial setting, using the allocentric-egocentric strategy switching task in the cross-shaped maze. We demonstrate that bilateral inactivation of the vHPC impaired the ability to switch from allocentric to egocentric (Experiment 1), and from egocentric to allocentric (Experiment 2) spatial strategies, as noted by the increased number of trials to reach the learning criterion and of entries into incorrect arms. These results resembled the effects of PFC inactivation by TTX on behavioral flexibility (Experiment 3). Furthermore, TTX infusion in the vHPC did not affect allocentric or egocentric learning per se but the ability to switch between either spatial strategy. Remarkably, inactivation of the vHPC decreased the latency to select an arm during the transition from an allocentric to an egocentric strategy, suggesting that the vHPC might mediate impulsive choices during the acquisition of a novel task. Our results highlight an important role of the vHPC in mediating behavioral flexibility by, most likely, modulating proper PFC function.
- Published
- 2019
26. Neural function in DCC mutation carriers with and without mirror movements
- Author
-
Donatella Tampieri, Amanda Chalupa, Sylvia M. L. Cox, Michael D. Fox, Marco Leyton, Angélica Torres-Berrío, Daniel E. Vosberg, Hugo Théoret, Cecilia Flores, Roberta La Piana, Vincent Beaulé, Alvaro Pascual-Leone, Yu Zhang, Chawki Benkelfat, Kevin Larcher, Dominique Allard, Alain Dagher, Danielle Cooke, Ridha Joober, Guy A. Rouleau, Natalia Jaworska, Franco Lepore, and Myriam Srour
- Subjects
0301 basic medicine ,Adult ,Male ,Cerebellum ,Heterozygote ,medicine.medical_treatment ,Movement ,Pyramidal Tracts ,Biology ,Functional Laterality ,Corpus Callosum ,White matter ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,medicine ,Humans ,RNA, Messenger ,Research Articles ,Movement Disorders ,medicine.diagnostic_test ,Electromyography ,Functional Neuroimaging ,fungi ,Motor Cortex ,Brain ,Human brain ,Middle Aged ,DCC Receptor ,Evoked Potentials, Motor ,Magnetic Resonance Imaging ,Transcranial Magnetic Stimulation ,Transcranial magnetic stimulation ,030104 developmental biology ,medicine.anatomical_structure ,Neurology ,Corticospinal tract ,Mutation (genetic algorithm) ,Mutation ,Axon guidance ,Female ,Neurology (clinical) ,Functional magnetic resonance imaging ,Neuroscience ,030217 neurology & neurosurgery ,Research Article - Abstract
Objective Recently identified mutations of the axon guidance molecule receptor gene, DCC, present an opportunity to investigate, in living human brain, mechanisms affecting neural connectivity and the basis of mirror movements, involuntary contralateral responses that mirror voluntary unilateral actions. We hypothesized that haploinsufficient DCC+/- mutation carriers with mirror movements would exhibit decreased DCC mRNA expression, a functional ipsilateral corticospinal tract, greater "mirroring" motor representations, and reduced interhemispheric inhibition. DCC+/- mutation carriers without mirror movements might exhibit some of these features. Methods The participants (n = 52) included 13 DCC+/- mutation carriers with mirror movements, 7 DCC+/- mutation carriers without mirror movements, 13 relatives without the mutation or mirror movements, and 19 unrelated healthy volunteers. The multimodal approach comprised quantitative real time polymerase chain reaction, transcranial magnetic stimulation (TMS), functional magnetic resonance imaging (fMRI) under resting and task conditions, and measures of white matter integrity. Results Mirror movements were associated with reduced DCC mRNA expression, increased ipsilateral TMS-induced motor evoked potentials, increased fMRI responses in the mirroring M1 and cerebellum, and markedly reduced interhemispheric inhibition. The DCC+/- mutation, irrespective of mirror movements, was associated with reduced functional connectivity and white matter integrity. Interpretation Diverse connectivity abnormalities were identified in mutation carriers with and without mirror movements, but corticospinal effects and decreased peripheral DCC mRNA appeared driven by the mirror movement phenotype. ANN NEUROL 2019;85:433-442.
- Published
- 2019
27. H3K79me2 dynamics in medium spiny neurons mediate long-term behavioral and cell type-specific molecular effects of early life stress
- Author
-
Simone Sidoli, Eric J. Nestler, Deena M. Walker, Orna Issler, Hope Kronman, Caleb J. Browne, Benjamin A. Garcia, Arthur Godino, Catherine Jensen Pena, Philipp Mews, Yentl Y. van der Zee, Eric M. Parise, Rachael L. Neve, Aarthi Ramakrishnan, Angélica Torres-Berrío, Brittany F. Boyce, Li Shen, and Casey K. Lardner
- Subjects
Male ,0301 basic medicine ,Jumonji Domain-Containing Histone Demethylases ,Nucleus accumbens ,Medium spiny neuron ,Nucleus Accumbens ,Article ,Histones ,Social defeat ,Mice ,03 medical and health sciences ,Histone H3 ,0302 clinical medicine ,Transcriptional regulation ,Animals ,Histone Demethylases ,Neurons ,Regulation of gene expression ,biology ,Receptors, Dopamine D2 ,F-Box Proteins ,Receptors, Dopamine D1 ,General Neuroscience ,Histone-Lysine N-Methyltransferase ,DOT1L ,030104 developmental biology ,Histone ,Gene Expression Regulation ,biology.protein ,Neuroscience ,Stress, Psychological ,030217 neurology & neurosurgery - Abstract
Animals susceptible to chronic social defeat stress (CSDS) exhibit depression-related behaviors, and show aberrant transcription across several limbic brain regions. The nucleus accumbens (NAc) in particular shows unique susceptible versus resilient phenotypes at the transcriptional, neuroanatomical, and physiological levels. Early life stress (ELS) promotes susceptibility to CSDS in adulthood, but associated enduring changes in transcriptional control mechanisms in NAc have not yet been investigated. Here, we examined long-lasting changes in histone modifications induced in NAc by ELS and studied their underlying mechanisms in mediating heightened lifelong stress susceptibility in male and female mice. We identify dimethylation of lysine 79 of histone H3 (H3K79me2) and the enzymes that control this modification, selectively in D2-type medium spiny neurons, as crucial for the expression of ELS-induced stress susceptibility. We also map the site-specific regulation of this histone mark genome-wide, and reveal the transcriptional networks it modulates. Finally, we demonstrate the potential clinical relevance of this epigenetic mechanism by showing that systemic delivery of a small molecule inhibitor of H3K79me2 deposition reverses ELS-induced behavioral deficits.
- Published
- 2021
28. Sex-specific role for SLIT1 in regulating stress susceptibility
- Author
-
Angélica Torres-Berrío, Casey K. Lardner, Marine Salery, Lars M. T. Eijssen, Philipp Mews, Julia E. Duffy, Collin D. Teague, Bart P. F. Rutten, Eric M. Parise, Li Shen, Hope Kronman, Lyonna F. Parise, Laurence de Nijs, Orna Issler, Benoit Labonté, Yentl Y. van der Zee, Vishwendra Patel, Eric J. Nestler, Deena M. Walker, Caleb J. Browne, Catherine Jensen Pena, and Aarthi Ramakrishnan
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Anhedonia ,Ventromedial prefrontal cortex ,Prefrontal Cortex ,Anxiety ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Downregulation and upregulation ,Internal medicine ,Medicine ,Animals ,Prefrontal cortex ,Biological Psychiatry ,Depression (differential diagnoses) ,Gene knockdown ,Depressive Disorder, Major ,Sex Characteristics ,business.industry ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Major depressive disorder ,Female ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Background Major depressive disorder is a pervasive and debilitating syndrome characterized by mood disturbances, anhedonia, and alterations in cognition. While the prevalence of major depressive disorder is twice as high for women as men, little is known about the molecular mechanisms that drive sex differences in depression susceptibility. Methods We discovered that SLIT1, a secreted protein essential for axonal navigation and molecular guidance during development, is downregulated in the adult ventromedial prefrontal cortex (vmPFC) of women with depression compared with healthy control subjects, but not in men with depression. This sex-specific downregulation of Slit1 was also observed in the vmPFC of mice exposed to chronic variable stress. To identify a causal, sex-specific role for SLIT1 in depression-related behavioral abnormalities, we performed knockdown (KD) of Slit1 expression in the vmPFC of male and female mice. Results When combined with stress exposure, vmPFC Slit1 KD reflected the human condition by inducing a sex-specific increase in anxiety- and depression-related behaviors. Furthermore, we found that vmPFC Slit1 KD decreased the dendritic arborization of vmPFC pyramidal neurons and decreased the excitability of the neurons in female mice, effects not observed in males. RNA sequencing analysis of the vmPFC after Slit1 KD in female mice revealed an augmented transcriptional stress signature. Conclusions Together, our findings establish a crucial role for SLIT1 in regulating neurophysiological and transcriptional responses to stress within the female vmPFC and provide mechanistic insight into novel signaling pathways and molecular factors influencing sex differences in depression susceptibility.
- Published
- 2021
29. miR-218 in Adolescence Predicts and Mediates Vulnerability to Stress
- Author
-
Torres-Berrío, Angélica, primary, Morgunova, Alice, additional, Giroux, Michel, additional, Cuesta, Santiago, additional, Nestler, Eric J., additional, and Flores, Cecilia, additional
- Published
- 2021
- Full Text
- View/download PDF
30. Author Correction: Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons
- Author
-
Eric M. Parise, Li Shen, Orna Issler, Eric J. Nestler, Deena M. Walker, Caleb J. Browne, Benjamin A. Garcia, Casey K. Lardner, Catherine Jensen Pena, Simone Sidoli, Arthur Godino, Hope Kronman, Aarthi Ramakrishnan, Yentl Y. van der Zee, Rachael L. Neve, Philipp Mews, Brittany F. Boyce, and Angélica Torres-Berrío
- Subjects
General Neuroscience ,Cell type specific ,Early life stress ,Biology ,Medium spiny neuron ,Neuroscience ,Term (time) - Published
- 2021
31. The 43rd Annual Meeting of the Canadian College of Neuropsychopharmacology, November 4, 2021.
- Author
-
Torres-Berrío, Angélica, Ramakrishnan, Aarthi, Minier-Toribio, Angélica, Parise, Eric M., Martínez-Rivera, Freddyson J., Browne, Caleb J., Issler, Orna, van der Zee, Yentl Y., Sial, Omar, García, Benjamin, Helin, Kristian, Sidoli, Simone, Shen, Li, Nestler, Eric J., Yap, Sidney, Luki, Jessica, Hanstock, Christopher C., Seres, Peter, Shandro, Tami, and Hanstock, Sarah
- Subjects
- *
ABSTRACTING , *CONFERENCES & conventions , *PROFESSIONAL associations , *PSYCHOPHARMACOLOGY - Published
- 2022
- Full Text
- View/download PDF
32. miR-218 in adolescence predicts and mediates vulnerability to stress
- Author
-
Angélica Torres-Berrío, Alice Morgunova, Cecilia Flores, Santiago Cuesta, Eric J. Nestler, and Michel Giroux
- Subjects
Male ,0301 basic medicine ,Deleted in Colorectal Cancer ,media_common.quotation_subject ,Period (gene) ,Vulnerability ,Down-Regulation ,Prefrontal Cortex ,Article ,Social defeat ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Stress (linguistics) ,microRNA ,Animals ,Medicine ,Social Behavior ,Prefrontal cortex ,Biological Psychiatry ,Depression (differential diagnoses) ,media_common ,business.industry ,MicroRNAs ,030104 developmental biology ,Psychological resilience ,business ,Neuroscience ,Stress, Psychological ,030217 neurology & neurosurgery - Abstract
Adolescence is a period of increased vulnerability to psychiatric disorders including depression. Discovering novel biomarkers to identify individuals who are at high risk is very much needed. Our previous work shows that the microRNA miR-218 mediates susceptibility to stress and depression in adulthood, by targeting the Netrin-1 guidance cue receptor gene Dcc (Deleted in colorectal cancer) in the medial prefrontal cortex (mPFC). Here we investigated whether miR-218 regulates Dcc expression in adolescence and could serve as an early predictor of lifetime stress vulnerability. miR-218 expression in the mPFC increases from early adolescence to adulthood and correlates negatively with Dcc levels. In blood, postnatal miR-218 expression parallels changes occurring in the mPFC. Notably, circulating miR-218 levels in adolescence associate with vulnerability to social defeat stress in adulthood, with high levels associated with social avoidance severity. Indeed, downregulation of miR-218 in the mPFC in adolescence promotes resilience to stress in adulthood, indicating that adolescent miR-218 expression may serve both as a marker of risk and as a target for early interventions.
- Published
- 2020
33. Dopamine Axon Targeting in the Nucleus Accumbens in Adolescence Requires Netrin-1
- Author
-
Angélica Torres-Berrío, Amanda White, Giovanni Hernandez, Lauren M. Reynolds, Cecilia Flores, Dominique Nouel, Helen M. Cooper, Alice Morgunova, and Santiago Cuesta
- Subjects
0301 basic medicine ,Dendritic spine ,nucleus accumbens ,Nucleus accumbens ,Biology ,Medium spiny neuron ,Cell and Developmental Biology ,03 medical and health sciences ,0302 clinical medicine ,Dopamine ,Netrin ,medicine ,guidance cues ,cortical development ,Amphetamine ,Prefrontal cortex ,lcsh:QH301-705.5 ,Original Research ,fungi ,Cell Biology ,Ventral tegmental area ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,lcsh:Biology (General) ,030220 oncology & carcinogenesis ,dopamine innervation ,adolescence ,Neuroscience ,Developmental Biology ,medicine.drug - Abstract
The fine arrangement of neuronal connectivity during development involves the coordinated action of guidance cues and their receptors. In adolescence, the dopamine circuitry is still developing, with mesolimbic dopamine axons undergoing target-recognition events in the nucleus accumbens (NAcc), while mesocortical projections continue to grow toward the prefrontal cortex (PFC) until adulthood. This segregation of mesolimbic versus mesocortical dopamine pathways is mediated by the guidance cue receptor DCC, which signals dopamine axons intended to innervate the NAcc to recognize this region as their final target. Whether DCC-dependent mesolimbic dopamine axon targeting in adolescence requires the action of its ligand, Netrin-1, is unknown. Here we combined shRNA strategies, quantitative analysis of pre- and post-synaptic markers of neuronal connectivity, and pharmacological manipulations to address this question. Similar to DCC levels in the ventral tegmental area, Netrin-1 expression in the NAcc is dynamic across postnatal life, transitioning from high to low expression across adolescence. Silencing Netrin-1 in the NAcc in adolescence results in an increase in the expanse of the dopamine input to the PFC in adulthood, with a corresponding increase in the number of presynaptic dopamine sites. This manipulation also results in altered dendritic spine density and morphology of medium spiny neurons in the NAcc in adulthood and in reduced sensitivity to the behavioral activating effects of the stimulant drug of abuse, amphetamine. These cellular and behavioral effects mirror those induced by Dcc haploinsufficiency within dopamine neurons in adolescence. Dopamine targeting in adolescence requires the complementary interaction between DCC receptors in mesolimbic dopamine axons and Netrin-1 in the NAcc. Factors regulating either DCC or Netrin-1 in adolescence can disrupt mesocorticolimbic dopamine development, rendering vulnerability or protection to phenotypes associated with psychiatric disorders.
- Published
- 2020
34. Adolescent Social Isolation Reprograms the Medial Amygdala: Transcriptome and Sex Differences in Reward
- Author
-
Hannah M. Cates, Andrew P. Lipschultz, Li Shen, Georgia E. Hodes, Bin Zhang, Ashley M. Cunningham, Arthur Godino, Orna Issler, Yentl Y. van der Zee, Eric M. Parise, Aarthi Ramakrishnan, Catherine Jensen Pena, Angélica Torres-Berrío, Xianxiao Zhou, Eric J. Nestler, Deena M. Walker, Caleb J. Browne, Pamela J. Kennedy, and Rosemary C. Bagot
- Subjects
0303 health sciences ,Period (gene) ,CRYM ,Crystallin mu ,Biology ,Amygdala ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Gene expression ,medicine ,Anxiety ,Social isolation ,medicine.symptom ,Neuroscience ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
Adolescence is a sensitive window for reward- and stress-associated behavior. Although stress during this period causes long-term changes in behavior in males, how females respond is relatively unknown. Here we show that social isolation stress in adolescence, but not adulthood, induces persistent but opposite effects on anxiety- and cocaine-related behaviors in male vs. female mice, and that these effects are reflected in transcriptional profiles within the adult medial amygdala (meA). By integrating differential gene expression with co-expression network analyses, we identified crystallin mu (Crym), a thyroid-binding protein, as a key driver of these transcriptional profiles. Manipulation of Crym specifically within adult meA neurons recapitulates the behavioral and transcriptional effects of social isolation and re-opens a window of plasticity that is otherwise closed. Our results establish that meA is essential for sex-specific responses to stressful and rewarding stimuli through transcriptional programming that occurs during adolescence.
- Published
- 2020
35. Unraveling the epigenetic landscape of depression: focus on early life stress
- Author
-
Eric J. Nestler, Eric M. Parise, Orna Issler, and Angélica Torres-Berrío
- Subjects
Epigenomics ,early life stress ,Biology ,Chromatin remodeling ,noncoding RNA ,chromatin remodeling ,03 medical and health sciences ,0302 clinical medicine ,Genetic predisposition ,Animals ,Humans ,Genetic Predisposition to Disease ,histone modification ,Epigenetics ,Depressive Disorder ,DNA methylation ,Depression ,Epigenome ,Non-coding RNA ,State of the Art ,030227 psychiatry ,3. Good health ,Chromatin ,Histone ,biology.protein ,Neuroscience ,Stress, Psychological - Abstract
Depression is a devastating psychiatric disorder caused by a combination of genetic predisposition and life events, mainly exposure to stress. Early life stress (ELS) in particular is known to "scar" the brain, leading to an increased susceptibility to developing depression later in life via epigenetic mechanisms. Epigenetic processes lead to changes in gene expression that are not due to changes in DNA sequence, but achieved via modulation of chromatin modifications, DNA methylation, and noncoding RNAs. Here we review common epigenetic mechanisms including the enzymes that take part in reading, writing, and erasing specific epigenetic marks. We then describe recent developments in understanding how ELS leads to changes in the epigenome that are manifested in increased susceptibility to depression-like abnormalities in animal models. We conclude with highlighting the need for future studies that will potentially enable the utilisation of the understanding of epigenetic changes linked to ELS for the development of much-needed novel therapeutic strategies and biomarker discovery. .La depresión es un trastorno psiquiátrico devastador causado por una combinación de una predisposición genética y de acontecimientos vitales, en que destaca la exposición al estrés. Se sabe que el estrés en los inicios de la vida (EIV) deja una “cicatriz” en el cerebro, lo que lleva a un aumento de la susceptibilidad para desarrollar una depresión en años posteriores a través de mecanismos epigenéticos. Los procesos epigenéticos conducen a cambios en la expresión génica que no se deben a cambios en la secuencia de ADN, sino que ocurren mediante la modulación de las modificaciones de la cromatina, de la metilación del ADN y de los ARNs no codificantes. En este artículo se revisan los mecanismos epigenéticos comunes, incluyendo las enzimas que participan en la lectura, la escritura y el borrado de marcas epigenéticas específicas. Luego se describen los desarrollos recientes en la comprensión de cómo el EIV produce cambios en el epigenoma, lo que se manifiesta -en modelos animales- en una mayor susceptibilidad a anormalidades similares a la depresión. Se finaliza destacando la necesidad de futuros estudios que potencialmente permitan utilizar la comprensión de los cambios epigenéticos relacionados con el EIV para el desarrollo de muy necesarias nuevas estrategias terapéuticas y el descubrimiento de biomarcadores.La dépression, trouble psychiatrique destructeur, est provoquée par une association de prédisposition génétique et d’événements de vie, principalement l’exposition au stress. Le stress de début de vie est particulièrement connu pour laisser une « cicatrice » au cerveau, le rendant plus susceptible de développer une dépression ultérieure par le biais de mécanismes épigénétiques. Les processus épigénétiques entraînent des modifications de l’expression génique qui ne sont pas dues à des changements de séquence ADN mais qui apparaissent par modulation des modifications de la chromatine, par méthylation de l’ADN et par des ARN non codants. Nous analysons dans cet article les mécanismes épigénétiques courants, dont les enzymes impliquées dans la lecture, l’écriture et l’effacement de marques épigénétiques spécifiques. Ainsi que nous le décrivons ensuite, des avancées récentes nous permettent de comprendre comment le stress de début de vie modifie l’épigénome en augmentant la susceptibilité aux anomalies de la dépression dans les modèles animaux. Nous en concluons que de nouvelles études sont nécessaires qui pourraient utiliser cette compréhension des modifications épigénétiques liées au stress de début de vie pour développer d’indispensables nouvelles stratégies thérapeutiques et la découverte de biomarqueurs.
- Published
- 2020
36. The Netrin-1/DCC Guidance Cue Pathway as a Molecular Target in Depression: Translational Evidence
- Author
-
Cecilia Flores, Eric J. Nestler, Giovanni Hernandez, and Angélica Torres-Berrío
- Subjects
0301 basic medicine ,Receptors, Cell Surface ,Biology ,Article ,03 medical and health sciences ,0302 clinical medicine ,microRNA ,Netrin ,medicine ,Humans ,Prefrontal cortex ,Biological Psychiatry ,Depression (differential diagnoses) ,Depressive Disorder, Major ,Mechanism (biology) ,Depression ,Tumor Suppressor Proteins ,fungi ,Netrin-1 ,medicine.disease ,DCC Receptor ,Axons ,MicroRNAs ,030104 developmental biology ,nervous system ,Molecular targets ,Biomarker (medicine) ,Major depressive disorder ,Cues ,Neuroscience ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
The Netrin-1/DCC guidance cue pathway plays a critical role in guiding growing axons toward the prefrontal cortex during adolescence and in the maturational organization and adult plasticity of prefrontal cortex connectivity. In this review, we put forward the idea that alterations in prefrontal cortex architecture and function, which are intrinsically linked to the development of major depressive disorder, originate in part from the dysregulation of the Netrin-1/DCC pathway by a mechanism that involves microRNA-218. We discuss evidence derived from mouse models of stress and from human postmortem brain and genome-wide association studies indicating an association between the Netrin-1/DCC pathway and major depressive disorder. We propose a potential role of circulating microRNA-218 as a biomarker of stress vulnerability and major depressive disorder.
- Published
- 2019
37. DCC Receptors Drive Prefrontal Cortex Maturation by Determining Dopamine Axon Targeting in Adolescence
- Author
-
Esther Del Cid Pellitero, Bryan Kolb, Paul Krimpenfort, Lauren M. Reynolds, Angélica Torres-Berrío, Laura C. Lambert, Matthew Pokinko, Cecilia Flores, Colleen Manitt, Santiago Cuesta, and Michael Wodzinski
- Subjects
Male ,0301 basic medicine ,Prefrontal Cortex ,Striatum ,Nucleus accumbens ,Nucleus Accumbens ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Dopamine ,Netrin ,medicine ,Animals ,Attention ,Axon ,Maze Learning ,Prefrontal cortex ,Biological Psychiatry ,Behavior, Animal ,Dopaminergic Neurons ,Dopaminergic ,Cognitive flexibility ,DCC Receptor ,Axons ,Inhibition, Psychological ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,Gene Knockdown Techniques ,Set, Psychology ,Psychology ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Background Dopaminergic input to the prefrontal cortex (PFC) increases throughout adolescence and, by establishing precisely localized synapses, calibrates cognitive function. However, why and how mesocortical dopamine axon density increases across adolescence remains unknown. Methods We used a developmental application of axon-initiated recombination to label and track the growth of dopamine axons across adolescence in mice. We then paired this recombination with cell-specific knockdown of the netrin-1 receptor DCC to determine its role in adolescent dopamine axon growth. We then assessed how altering adolescent PFC dopamine axon growth changes the structural and functional development of the PFC by quantifying pyramidal neuron morphology and cognitive performance. Results We show, for the first time, that dopamine axons continue to grow from the striatum to the PFC during adolescence. Importantly, we discover that DCC, a guidance cue receptor, controls the extent of this protracted growth by determining where and when dopamine axons recognize their final target. When DCC-dependent adolescent targeting events are disrupted, dopamine axons continue to grow ectopically from the nucleus accumbens to the PFC and profoundly change PFC structural and functional development. This leads to alterations in cognitive processes known to be impaired across psychiatric conditions. Conclusions The prolonged growth of dopamine axons represents an extraordinary period for experience to influence their adolescent trajectory and predispose to or protect against psychopathology. DCC receptor signaling in dopamine neurons is a molecular link where genetic and environmental factors may interact in adolescence to influence the development and function of the prefrontal cortex.
- Published
- 2018
38. Non-Contingent Exposure to Amphetamine in Adolescence Recruits miR-218 to Regulate Dcc Expression in the VTA
- Author
-
Dominique Nouel, Angélica Torres-Berrío, Cecilia Flores, Andreas Arvanitogiannis, Santiago Cuesta, José Maria Restrepo-Lozano, Lauren M. Reynolds, and Steven Silvestrin
- Subjects
Male ,0301 basic medicine ,medicine.medical_treatment ,Gene Expression ,Biology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Dopamine ,Dopamine receptor D2 ,microRNA ,medicine ,Animals ,Prefrontal cortex ,Amphetamine ,Pharmacology ,Dopaminergic Neurons ,Ventral Tegmental Area ,fungi ,Age Factors ,DCC Receptor ,Mice, Inbred C57BL ,Stimulant ,Ventral tegmental area ,MicroRNAs ,Psychiatry and Mental health ,030104 developmental biology ,medicine.anatomical_structure ,Central Nervous System Stimulants ,Original Article ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
The development of the dopamine input to the medial prefrontal cortex occurs during adolescence and is a process that is vulnerable to disruption by stimulant drugs such as amphetamine. We have previously linked the amphetamine-induced disruption of dopamine connectivity and prefrontal cortex maturation during adolescence to the downregulation of the Netrin-1 receptor, DCC, in dopamine neurons. However, how DCC expression in dopamine neurons is itself regulated is completely unknown. MicroRNA (miRNA) regulation of mRNA translation and stability is a prominent mechanism linking environmental events to changes in protein expression. Here, using male mice, we show that miR-218 is expressed in dopamine neurons and is a repressor of DCC. Whereas Dcc mRNA levels increase from early adolescence to adulthood, miR-218 exhibits the exact opposite switch, most likely maintaining postnatal Dcc expression. This dynamic regulation appears to be selective to Dcc since the expression of Robo 1, the other guidance cue receptor target of miR-218, does not vary with age. Amphetamine in adolescence, but not in adulthood, increases miR-218 in the VTA and this event is required for drug-induced downregulation of Dcc mRNA and protein expression. This effect seems to be specific to Dcc because amphetamine does not alter Robo1. Furthermore, the upregulation of miR-218 by amphetamine requires dopamine D2 receptor activation. These findings identify miR-218 as regulator of DCC in the VTA both in normal development and after drug exposure in adolescence.
- Published
- 2017
39. The Netrin-1/DCC Guidance Cue Pathway as a Molecular Target in Depression: Translational Evidence
- Author
-
Torres-Berrío, Angélica, primary, Hernandez, Giovanni, additional, Nestler, Eric J., additional, and Flores, Cecilia, additional
- Published
- 2020
- Full Text
- View/download PDF
40. Dopamine Axon Targeting in the Nucleus Accumbens in Adolescence Requires Netrin-1
- Author
-
Cuesta, Santiago, primary, Nouel, Dominique, additional, Reynolds, Lauren M., additional, Morgunova, Alice, additional, Torres-Berrío, Angélica, additional, White, Amanda, additional, Hernandez, Giovanni, additional, Cooper, Helen M., additional, and Flores, Cecilia, additional
- Published
- 2020
- Full Text
- View/download PDF
41. miR-218 in adolescence predicts and mediates vulnerability to stress
- Author
-
Torres-Berrío, Angélica, primary, Morgunova, Alice, additional, Giroux, Michel, additional, Cuesta, Santiago, additional, Nestler, Eric J., additional, and Flores, Cecilia, additional
- Published
- 2020
- Full Text
- View/download PDF
42. Sex-Specific Role for the Long Non-coding RNA LINC00473 in Depression
- Author
-
Issler, Orna, primary, van der Zee, Yentl Y., additional, Ramakrishnan, Aarthi, additional, Wang, Junshi, additional, Tan, Chunfeng, additional, Loh, Yong-Hwee E., additional, Purushothaman, Immanuel, additional, Walker, Deena M., additional, Lorsch, Zachary S., additional, Hamilton, Peter J., additional, Peña, Catherine J., additional, Flaherty, Erin, additional, Hartley, Brigham J., additional, Torres-Berrío, Angélica, additional, Parise, Eric M., additional, Kronman, Hope, additional, Duffy, Julia E., additional, Estill, Molly S., additional, Calipari, Erin S., additional, Labonté, Benoit, additional, Neve, Rachael L., additional, Tamminga, Carol A., additional, Brennand, Kristen J., additional, Dong, Yan, additional, Shen, Li, additional, and Nestler, Eric J., additional
- Published
- 2020
- Full Text
- View/download PDF
43. Unraveling the epigenetic landscape of depression: focus on early life stress
- Author
-
Torres-Berrío, Angélica, primary, Issler, Orna, additional, Parise, Eric M., additional, and Nestler, Eric J., additional
- Published
- 2019
- Full Text
- View/download PDF
44. Oxycodone‐induced gene expression adaptations in the brain reward center in a murine model of neuropathic pain
- Author
-
Claire Polizu, Kerri D. Pryce, Angélica Torres-Berrío, Li Shen, Hope Kronman, Aarthi Ramakrishnan, Venetia Zachariou, Eric J. Nestler, and Catherine Jensen Pena
- Subjects
business.industry ,Biochemistry ,Murine model ,Neuropathic pain ,Gene expression ,Genetics ,Medicine ,Brain stimulation reward ,Center (algebra and category theory) ,business ,Molecular Biology ,Oxycodone ,Neuroscience ,Biotechnology ,medicine.drug - Published
- 2019
45. MiR-218: A Molecular Switch and Potential Biomarker of Susceptibility to Stress
- Author
-
José Maria Restrepo-Lozano, Dominique Nouel, Angélica Torres-Berrío, Santiago Cuesta, Pier Larochelle, Eric J. Nestler, Eric M. Parise, and Cecilia Flores
- Subjects
Male ,0301 basic medicine ,Down-Regulation ,Prefrontal Cortex ,Biology ,behavioral disciplines and activities ,Article ,Social Defeat ,Social defeat ,Mice ,Cellular and Molecular Neuroscience ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Animals ,Chronic stress ,Prefrontal cortex ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,musculoskeletal, neural, and ocular physiology ,Up-Regulation ,MicroRNAs ,Psychiatry and Mental health ,030104 developmental biology ,nervous system ,Potential biomarkers ,Single session ,Neuroscience ,Biomarkers ,Stress, Psychological ,030217 neurology & neurosurgery ,psychological phenomena and processes - Abstract
Low miR-218 expression in the medial prefrontal cortex (mPFC) is a consistent trait of depression. Here we assessed whether miR-218 in the mPFC confers resilience or susceptibility to depression-like behaviors in adult mice, using the chronic social defeat stress (CSDS) model of depression. We also investigated whether stress-induced variations of miR-218 expression in the mPFC can be detected in blood. We find that downregulation of miR-218 in the mPFC increases susceptibility to a single session of social defeat, whereas overexpression of miR-218 selectively in mPFC pyramidal neurons promotes resilience to CSDS and prevents stress-induced morphological alterations to those neurons. After CSDS, susceptible mice have low levels of miR-218 in the blood as compared to control or resilient groups. We show further that up-and downregulation of miR-218 levels specifically in the mPFC correlates with miR-218 expression in blood. Our results suggest that miR-218 in the adult mPFC might function as a molecular switch that determines susceptibility versus resilience to chronic stress, and that stress-induced variations in mPFC levels of miR-218 could be detected in blood. We propose that blood expression of miR-218 might serve as potential readout of vulnerability to stress and as a proxy of mPFC function.
- Published
- 2019
- Full Text
- View/download PDF
46. Interaction Between Stress and Addiction: Contributions From Latin-American Neuroscience
- Author
-
Angélica Torres-Berrío, Silvia Lopez-Guzman, Santiago Cuesta, and Mauricio O. Nava-Mesa
- Subjects
0301 basic medicine ,Neural substrate ,media_common.quotation_subject ,lcsh:BF1-990 ,mesocorticolimbic pathway ,Addiction ,Review ,Stress ,Affect (psychology) ,Heroin ,stress ,03 medical and health sciences ,Reward system ,0302 clinical medicine ,medicine ,Psychology ,Chronic stress ,Mesocorticolimbic pathway ,General Psychology ,media_common ,biology ,biomarkers ,CRF ,Abstinence ,biology.organism_classification ,Latin America ,lcsh:Psychology ,030104 developmental biology ,addiction ,Cannabis ,Neuroscience ,Biomarkers ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Drug addiction is a chronic neuropsychiatric disorder that escalates from an initial exposure to drugs of abuse, such as cocaine, cannabis, or heroin, to compulsive drug-seeking and intake, reduced ability to inhibit craving-induced behaviors, and repeated cycles of abstinence and relapse. It is well-known that chronic changes in the brain's reward system play an important role in the neurobiology of addiction. Notably, environmental factors such as acute or chronic stress affect this system, and increase the risk for drug consumption and relapse. Indeed, the HPA axis, the autonomic nervous system, and the extended amygdala, among other brain stress systems, interact with the brain's reward circuit involved in addictive behaviors. There has been a growing interest in studying the molecular, cellular, and behavioral mechanisms of stress and addiction in Latin-America over the last decade. Nonetheless, these contributions may not be as strongly acknowledged by the broad scientific audience as studies coming from developed countries. In this review, we compile for the first time a series of studies conducted by Latin American-based neuroscientists, who have devoted their careers to studying the interaction between stress and addiction, from a neurobiological and clinical perspective. Specific contributions about this interaction include the study of CRF receptors in the lateral septum, investigations on the neural mechanisms of cross-sensitization for psychostimulants and ethanol, the identification of the Wnt/?-catenin pathway as a critical neural substrate for stress and addiction, and the emergence of the cannabinoid system as a promising therapeutic target. We highlight animal and human studies, including for instance, reports coming from Latin American laboratories on single nucleotide polymorphisms in stress-related genes and potential biomarkers of vulnerability to addiction, that aim to bridge the knowledge from basic science to clinical research. © 2018 Torres-Berrio, Cuesta, Lopez-Guzman and Nava-Mesa.
- Published
- 2018
47. Sex-Specific Role for the Long Non-coding RNA LINC00473 in Depression
- Author
-
Yentl Y. van der Zee, Li Shen, Catherine Jensen Pena, Yan Dong, Orna Issler, Angélica Torres-Berrío, Benoit Labonté, Zachary S. Lorsch, Chunfeng Tan, Julia E. Duffy, Brigham J. Hartley, Kristen J. Brennand, Eric M. Parise, Erin Flaherty, Junshi Wang, Peter J. Hamilton, Yong-Hwee E. Loh, Immanuel Purushothaman, Rachael L. Neve, Eric J. Nestler, Deena M. Walker, Hope Kronman, Aarthi Ramakrishnan, Molly Estill, Erin S. Calipari, Carol A. Tamminga, Psychiatrie & Neuropsychologie, and RS: MHeNs - R3 - Neuroscience
- Subjects
Male ,0301 basic medicine ,STRESS ,PREFRONTAL CORTEX ,SUSCEPTIBILITY ,Social defeat ,Mice ,0302 clinical medicine ,SOCIAL DEFEAT ,Gene expression ,RNA-Seq ,TRANSCRIPTION ,Prefrontal cortex ,Aged, 80 and over ,Neurons ,Behavior, Animal ,biology ,Depression ,Effector ,General Neuroscience ,LOCALIZATION ,Middle Aged ,Resilience, Psychological ,Phenotype ,Long non-coding RNA ,Female ,RNA, Long Noncoding ,Adult ,medicine.medical_specialty ,Down-Regulation ,UNIQUE FEATURES ,Mice, Transgenic ,CREB ,Young Adult ,03 medical and health sciences ,Sex Factors ,Internal medicine ,medicine ,Animals ,Humans ,Gene ,Aged ,Depressive Disorder, Major ,GENOME-WIDE ,EVOLUTION ,030104 developmental biology ,Endocrinology ,CELLS ,biology.protein ,Stress, Psychological ,030217 neurology & neurosurgery - Abstract
Depression is a common disorder that affects women at twice the rate of men. Here, we report that long non-coding RNAs (lncRNAs), a recently discovered class of regulatory transcripts, represent about one-third of the differentially expressed genes in the brains of depressed humans and display complex region- and sex-specific patterns of regulation. We identified the primate-specific, neuronal-enriched gene LINC00473 as downregulated in prefrontal cortex (PFC) of depressed females but not males. Using viral-mediated gene transfer to express LINC00473 in adult mouse PFC neurons, we mirrored the human sex-specific phenotype by inducing stress resilience solely in female mice. This sex-specific phenotype was accompanied by changes in synaptic function and gene expression selectively in female mice and, along with studies of human neuron-like cells in culture, implicates LINC00473 as a CREB effector. Together, our studies identify LINC00473 as a female-specific driver of stress resilience that is aberrant in female depression. Issler et al. demonstrate that long non-coding RNAs are robustly regulated in the brains of postmortem depressed humans in a brain site- and sex-specific manner. LINC00473 is highlighted as key regulator of mood in females only, where it acts in prefrontal cortex by regulating gene expression, neurophysiology, and behavior.
- Published
- 2020
48. The opioid system in stress-induced memory disorders: From basic mechanisms to clinical implications in post-traumatic stress disorder and Alzheimer's disease
- Author
-
Angélica Torres-Berrío and Mauricio O. Nava-Mesa
- Subjects
Sympathetic nervous system ,Review ,Disease ,Emotional disorder ,Opiate ,Cognition ,Opioid system ,0302 clinical medicine ,Pathology ,Limbic System ,Medicine ,Chronic stress ,Opiate receptor ,Symptomatology ,Acute stress ,Neuropsychiatric stress disorders ,Traumatic stress ,Posttraumatic stress disorder ,Brain region ,3. Good health ,Mental stress ,medicine.anatomical_structure ,Opioid Peptides ,Memory disorders ,Adrenergic system ,Memory disorder ,Alzheimer disease ,Opioid peptides ,Human ,medicine.drug ,Memory Dysfunction ,Context (language use) ,Stress ,Hypothalamus hypophysis adrenal system ,03 medical and health sciences ,Limbic system ,Memory ,Alzheimer Disease ,Animals ,Humans ,Biological Psychiatry ,Pharmacology ,Memory Disorders ,Animal ,business.industry ,Nonhuman ,030227 psychiatry ,Metabolism ,Opioid ,psychological ,business ,Complication ,Neuroscience ,Stress, Psychological ,Opiate peptide - Abstract
Cognitive and emotional impairment are a serious consequence of stress exposure and are core features of neurological and psychiatric conditions that involve memory disorders. Indeed, acute and chronic stress are high-risk factors for the onset of post-traumatic stress disorder (PTSD) and Alzheimer's disease (AD), two devastating brain disorders associated with memory dysfunction. Besides the sympathetic nervous system and the hypothalamic–pituitary–adrenal (HPA) axis, stress response also involves the activation of the opioid system in brain regions associated with stress regulation and memory processing. In this context, it is possible that stress-induced memory disorders may be attributed to alterations in the interaction between the neuroendocrine stress system and the opioid system. In this review, we: (1) describe the effects of acute and chronic stress on memory, and the modulatory role of the opioid system, (2) discuss the contribution of the opioid system to the pathophysiology of PTSD and AD, and (3) present evidence of current and potential therapies that target the opioid receptors to treat PTSD- and AD-associated symptoms. © 2018 The Authors
- Published
- 2018
49. MiR-218: a molecular switch and potential biomarker of susceptibility to stress
- Author
-
Torres-Berrío, Angélica, primary, Nouel, Dominique, additional, Cuesta, Santiago, additional, Parise, Eric M., additional, Restrepo-Lozano, José María, additional, Larochelle, Pier, additional, Nestler, Eric J., additional, and Flores, Cecilia, additional
- Published
- 2019
- Full Text
- View/download PDF
50. The ventral hippocampus is required for behavioral flexibility but not for allocentric/egocentric learning
- Author
-
Torres-Berrío, Angélica, primary, Vargas-López, Viviana, additional, and López-Canul, Martha, additional
- Published
- 2019
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.