Nicole Leite Galvão-Coelho

Social isolation disrupts hippocampal neurogenesis in young non-human primates

Social relationships are crucial for the development and maintenance of normal behavior in non-human primates. Animals that are raised in isolation develop abnormal patterns of behavior that persist even when they are later reunited with their parents. In rodents, social isolation is a stressful event and is associated with a decrease in hippocampal neurogenesis but considerably less is known about the effects of social isolation in non-human primates during the transition from adolescence to adulthood. To investigate how social isolation affects young marmosets, these were isolated from other members of the colony for 1 or 3 weeks and evaluated for alterations in their behavior and hippocampal cell proliferation. We found that anxiety-related behaviors like scent-marking and locomotor activity increased after social isolation when compared to baseline levels. In agreement, grooming—an indicative of attenuation of tension—was reduced among isolated marmosets. These results were consistent with increased cortisol levels after 1 and 3 weeks of isolation. After social isolation (1 or 3 weeks), reduced proliferation of neural cells in the subgranular zone of dentate granule cell layer was identified and a smaller proportion of BrdU-positive cells underwent neuronal fate (doublecortin labeling). Our data is consistent with the notion that social deprivation during the transition from adolescence to adulthood leads to stress and produces anxiety-like behaviors that in turn might affect neurogenesis and contribute to the deleterious consequences of prolonged stressful conditions.

The Therapeutic Potentials of Ayahuasca in the Treatment of Depression

Major depressive disorder (MDD) is generally classified as a mood disorder with a profound effect on the individual’s behavior and quality of life. According to the World Health Organization, in about 20 years, depression will be the disorder with the most significant repercussions, both socially and economically. Despite the substantial progress in the development of new antidepressants, their effectiveness remains low, with remission of about 50 % after a single regime of treatment. The most common form of pharmacological treatment of MDD is based on selective serotonin reuptake inhibitors (SSRIs), designed to increase extracellular levels of the neurotransmitter serotonin. Unfortunately, antidepressants currently available based on SSRIs may take several weeks to achieve the desired therapeutic effects. Therefore, massive effort has been devoted to find alternative treatments for MDD. For example, the use of ketamine, of (±)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI), and β-carbolines is under current investigation. Based on evidence from the literature and a pilot study conducted by our group, we speculate about the possible therapeutic potential of ayahuasca for MDD. In part, such conjecture is based on the fact that ayahuasca combines N,N-dimethyltryptamine (DMT), acting particularly on serotonin neurotransmission through 5-HT2A receptors and monoamine oxidase inhibitors (MAOI), both involved, at least indirectly, with pharmacological formulations intended for MDD treatment. In this chapter, we will review the major aspects of MDD such as diagnosis, current pharmacological treatments, and the motivations to use ayahuasca as a novel alternative.

The Influence of Sex and Relatedness on Stress Response in Common Marmosets (Callithrix jacchus)

Research in stress physiology has demonstrated the benefits of receiving social support during stressful conditions. However, recent data have shown that the efficacy of social support in buffering physiological and behavioral responses to stressor agents depends on species, sex, and relatedness among animals. This study investigated whether different kinds of social support (presence of same sex related or nonrelated conspecifics) have the same effect on hormonal (fecal cortisol levels) and behavioral responses (agonistic: scent‐marking and individual piloerection; anxiety: locomotion; tension‐reducing: autogrooming, allogrooming, and body contact). We used adult male and female isosexual dyads of Callithrix jacchus, a small Neotropical primate from the Callitrichidae family, widely used in the study of stress and related diseases. Following a 28‐day baseline phase, dyads faced three challenging situations (phase 1: dyads were moved together from the baseline cage to a similar new cage; phase 2: each dyad member was moved alone to a new cage; and phase 3: dyad members were reunited in the same baseline cage). Type of social support was found to influence the response to stressors differently for each sex. Related male dyads did not change their hormonal or behavioral profile over the three experimental phases, when compared to the baseline phase. For nonrelated male dyads, social support buffered hormonal but not behavioral response. For females, the social support offered by a related and nonrelated animal, does not seem to buffer the stress response, as shown by correlations between agonistic behaviors versus cortisol and locomotion during all three experimental phases and a significant increase in fecal cortisol levels during phases 2 and 3, when compared with baseline levels. The results only partially support the buffering model theory and corroborate other studies reporting that the benefits of social support during a period of crisis arise only when it is adaptive for that species. Am. J. Primatol. 74:819‐827, 2012.

A randomized placebo-controlled trial on the antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression

Major Depressive Disorder affects about 350 million people worldwide, and about one-third of the patients are considered treatment-resistant. Furthermore, available antidepressants take usually two weeks for the onset of their antidepressant effect. Recent open label trials show that psychedelics, such as ayahuasca and psilocybin, hold promise as fast-onset antidepressants. Although promising, these studies were not controlled for the placebo effect. To address this issue, and to further test the antidepressant effects of ayahuasca, we conducted a parallel arm, double-blind randomised placebo-controlled trial, in patients with treatment-resistant major depression. Thirty-five patients with treatment-resistant major depression received a single dose of ayahuasca or placebo. We measured as primary outcome the change in the Hamilton Depression Rating scale (HAM-D) seven days after the dosing session, and as secondary outcomes the changes in Montgomery–Åsberg Depression Rating Scale (MADRS), and response rates at one day (D1), two days (D2) and seven days (D7) after dosing, and remission rates at D7. This study is registered with http://clinicaltrials.gov (NCT02914769). We observed robust evidence of rapid antidepressant effects of a single dosing session with ayahuasca when compared to placebo. HAM-D scores at D7 were significantly lower in patients treated with ayahuasca than in those treated with placebo (p=0·019; Cohen’s d=0·98). MADRS scores were significantly reduced in the ayahuasca group compared to the placebo group at all endpoints (at D1 and D2, p=0·04; at D7, p<0·0001). Between-group effect sizes increased from D1 to D7 (D1: Cohen’s d=0·84; D2: Cohen’s d=0·84; D7: Cohen’s d=1·49). Response rates were high for both groups at D1 and D2, and were significantly higher in the ayahuasca group only at D7 (64% vs. 27%; OR = 4·95; p = 0·04; NNT = 2·66). Remission rate was not significantly different between groups. Our study provides new evidence of rapid antidepressant effects of ayahuasca for treatment-resistant major depression.Recent open label trials show that psychedelics, such as ayahuasca, hold promise as fast-onset antidepressants in treatment-resistant depression. In order to further test the antidepressant effects of ayahuasca, we conducted a parallel-arm, double-blind randomized placebo-controlled trial in 29 patients with treatment-resistant depression. Patients received a single dose of either ayahuasca or placebo. Changes in depression severity were assessed with the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating scale (HAM-D). Assessments were made at baseline, and at one (D1), two (D2) and seven (D7) days after dosing. We observed significant antidepressant effects of ayahuasca when compared to placebo at all timepoints. MADRS scores were significantly lower in the ayahuasca group compared to placebo (at D1 and D2: p=0.04; and at D7: p<0.0001). Between-group effect sizes increased from D1 to D7 (D1: Cohens d=0.84; D2: Cohens d=0.84; D7: Cohens d=1.49). Response rates were high for both groups at D1 and D2, and significantly higher in the ayahuasca group at D7 (64% vs. 27%; p=0.04), while remission rate was marginally significant at D7 (36% vs. 7%, p=0.054). To our knowledge, this is the first controlled trial to test a psychedelic substance in treatment-resistant depression. Overall, this study brings new evidence supporting the safety and therapeutic value of ayahuasca, dosed within an appropriate setting, to help treat depression. Clinical trial registration ID #NCT02914769

Endocrine and Cognitive Adaptations to Cope with Stress in Immature Common Marmosets (Callithrix jacchus): Sex and Age Matter

Phenotypic sex differences in primates are associated with body differentiation during the early stages of life, expressed in both physiological and behavioral features. Hormones seem to play a pivotal role in creating a range of responses to meet environmental and social demands, resulting in better reactions to cope with challenges to survival and reproduction. Steroid hormones actively participate in neuroplasticity and steroids from both gonads and neurons seem to be involved in behavioral modulation in primates. Indirect evidence suggests the participation of sexual steroids in dimorphism of the stress response in common marmosets. This species is an important experimental model in psychiatry, and we found a dual profile for cortisol in the transition from juvenile to subadult, with females showing higher levels. Immature males and females at 6 and 9 months of age moved alone from the family group to a new cage, over a 21-day period, expressed distinct patterns of cortisol variation with respect to range and duration of response. Additional evidence showed that at 12 months of age, males and females buffered the hypothalamic–pituitary–adrenal axis during chronic stress. Moreover, chronic stressed juvenile marmoset males showed better cognitive performance in working memory tests and motivation when compared to those submitted to short-term stress living in family groups. Thus, as cortisol profile seems to be sexually dimorphic before adulthood, age and sex are critical variables to consider in approaches that require immature marmosets in their experimental protocols. Moreover, available cognitive tests should be scrutinized to allow better investigation of cognitive traits in this species.

Resposta ao estresse: I. Homeostase e teoria da alostase

Os seres vivos desenvolvem ao longo de sua historia evolutiva mecanismos de enfrentamento as condicoes adversas originadas tanto no ambiente geofisico como no ambiente social. Esta resposta adaptativa e coordenada e envolve diferentes sistemas funcionais, particularmente, os sistemas nervoso, endocrino e imune, e e denominada de resposta ao estresse e deve atender a duas demandas principais da vida: sobrevivencia e reproducao. Esta revisao tem o objetivo de discutir o emprego do conceito classico de homeostase e um conceito alternativo, alostase, que inclui os mecanismos preditivos e reativos de regulacao, assim como os diferentes niveis de impacto dos estressores cronicos, resultando em sobrecarga alostatica que pode ou nao se seguir de falha alostatica. Os mecanismos neurais, hormonais, imunes, sistemicos e moleculares, que compreendem os sistemas alostaticos subjacentes a resposta ao estresse sao tambem apresentados.

Acute antidepressant effect of ayahuasca in juvenile non-human primate model of depression.

The incidence of major depression in adolescents, aged between 15 to 18 years, reaches approximately 14%. Usually, this disorder presents a recurrent way, without remission of symptoms even after several pharmacological treatments, persisting through adult life. Due to the relatively low efficacy of commercially available antidepressant, new pharmacological therapies are under continuous exploration. Recent evidence suggests that classic psychedelics, such as ayahuasca, produce rapid and robust antidepressant effects in treatment-resistant depression patients. In this study, we evaluated the potential of antidepressant effects of ayahuasca in a juvenile model of depression in a non-human primate, common marmoset (Callithrix jacchus). The model induces depressive-like symptoms by chronic social isolation (60 days) and antidepressant effects monitoring included fecal cortisol, body weight, and behavioral parameters. The animals presented hypocortisolemia and the recovery of cortisol to baseline levels started already at 24h after the ingestion of ayahuasca, but not the vehicle. Moreover, in males, ayahuasca, and not the vehicle, reduced the scratching, a stereotypic behavior, and increased the feeding. Ayahuasca also improving body weight to baseline levels in male and female common marmosets. The behavioral response induced by ayahuasca shows long effect, lasting 14 days. Therefore, for this translational animal model of juvenile depression, it could be proposed that ayahuasca treatment presented more notable antidepressant effects than tricyclic antidepressant nortriptyline, investigated by our group, using this same protocol in an anterior study. Ayahuasca produced faster and more durable effect on reversion of physiological changes and depressive-like symptoms. Therefore, the results found for ayahuasca treatment corroborates in the validation of this substance as an effective antidepressant drug and encourages the return of studies with psychedelic drugs in the treatment of humor disorders, including adolescents with early-age depression.

A Single Dose Of Ayahuasca Modulates Salivary Cortisol In Treatment-Resistant Depression

Major depression is a highly prevalent mood disorder, affecting about 350 million people, and around 30% of the patients are resistant to currently available antidepressant medications. Recent evidence from a randomized placebo-controlled trial supports the rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression. The aim of this study was to explore the effect of ayahuasca on plasma cortisol and awakening salivary cortisol response, in the same group of treatment-resistant patients and in healthy volunteers. Subjects received a single dose of ayahuasca or placebo, and both plasma and awakening salivary cortisol response were measured at baseline (before dosing) and 48h after the dosing session. Baseline assessment (D0) showed blunted awakening salivary cortisol response and hypocortisolemia in patients (DM), both with respect to healthy controls group (C). Salivary cortisol also was measured during dosing session and we observed a large increased for both C and DM that ingested ayahuasca, than placebo groups. After 48h of the dosing session (D2) with ayahuasca, awakening salivary cortisol response (for both sexes) of treated patients became similar to levels detected in controls. This was not observed in patients that ingested placebo. No changes in plasma cortisol were observed after 48 hours of ayahuasca or placebo ingestion for both groups and sexes. Therefore, these findings point to new evidence of modulation of ayahuasca on salivary cortisol levels, as cortisol acts in regulation of distinct physiological pathways, emotional and cognitive processes related to etiology of depression, this modulation could be an important part of the antidepressant effects observed with ayahuasca. Moreover, this study highlights the importance of psychedelics in the treatment of human mental disorders.

Social interactions and androgens levels in marmosets (Callithrix jacchus) in field and laboratory studies: A preliminary investigation of the Challenge Hypothesis

Living organisms need time and energy to perform basic activities in order to survive and reproduce, including growth, development, energy storage, maintenance of vital activities, and pathogen defenses, as well as mating and reproductive efforts during the life cycle (Dammhahn and Kappeler, 2012; Gittleman and Thompson, 1988). However, both time and energy are limited resources and trade-offs are necessary to optimize decisions about how to use them (Kaplan and Gangestad, 2005). Thus, the life history theory predicts that natural selection favors individuals that better allocate energy resources to promote lifetime reproductive success (Del Giudice et al, 2015; Ellison, 2017). In this context, one of the crucial trade-offs that needs to be managed is the cost of reproduction, involving mating effort versus parental effort (Muller, 2017). The endocrine system mediates the trade-offs for energy distribution since it exerts numerous simultaneous effects that allow a coordinated chain of action (Rodney, 2016). In relation to reproductive success, the hypothalamic-pituitary–gonadal axis plays a central role in vertebrates, and in males, testosterone affects sexual, aggressive, reproductive and metabolic functions. According to the Challenge Hypothesis (CH) (Wingfield et al, 1990), four contexts promote changes in testosterone secretion:(i) baseline production mainly devoted to maintaining physiological and reproductive functions; (ii) territorial-related social aggression, when testosterone increases beyond the basal levels, and (iii) male-male competition for receptive females where an additional increase is observed. However, during (iv) parental care, testosterone levels generally decline (Goymann et al., 2007; Wingfield, 2017). Thus, the main tradeoff proposed for androgen variation is increased testosterone in contexts of aggression and sexual interactions versus a decline in testosterone during parental care. Despite this significant trade-off, it is also important to underscore that the pattern of androgen secretion in response to sexual, parental and social contexts varies in different species. Since Wingfield et al. postulated the CH (Wingfield et al, 1990), a large number of field and laboratory studies have shown the importance of genes, age, season, time of day and social, physical and environmental characteristics in modulating the androgen response (Kempenaers et al, 2008). For instance, monogamous birds exhibit greater androgen responsiveness to social contexts than promiscuous birds (Hirschenhauser and Oliveira, 2006). In some species of nonhuman primates, the increase in testosterone during the breeding season correlates positively with levels of male-male aggression (Lemur catta: Cavigelli and Pereira, 2000; Eulemur fulvus: Ostner et al., 2002), whereas in others (Cebus apella, Lynch et al., 2002) it correlates with female receptivity during this period. Moreover, some species show no change in testosterone levels during the reproductive season (Brachyteles arachnoides: Strier et al., 1999) or during periods of social instability (Saguinus mystax: Huck et al., 2005), contradicting CH predictions. Therefore, reproduction frequency (seasonal or non-seasonal), type of mating system, degree of parental investment and levels of male-male aggression are important species-specific factors that modulate androgenic reactivity by influencing both the amplitude and duration of the response (Hau et al., 2008; Hirschenhauser et al. 2003; Hirschenhauser and Oliveira 2006; Kempenaers et al, 2008). In addition to the classical seasonal, male-male and male-female responses, Goymann et al. (2007) also revised the original CH to include changes in androgen levels associated with non-social environmental cues and the physiological capacity of animals to produce and secrete androgens. Additionally, change in androgen levels due to social isolation have also been studied, since in some species of birds, these levels rise during social isolation and decrease in social contexts

Resposta ao estresse: II. Resiliência e vulnerabilidade

A crescente exposicao a estressores na vida cotidiana aumentou significativamente a investigacao da resposta ao estresse nas duas ultimas decadas. Embora associada a consequencias negativas, pois muitas patologias fisicas e mentais sao desencadeadas por exposicao cronica a estressores, esta resposta e indispensavel para sobrevivencia do individuo e e extremamente adaptativa quando ativada de forma aguda. Na parte I desta revisao foram abordados os conceitos de homestase e alostase e os sistemas fisiologicos ativados durante a resposta ao estresse. Na parte II serao discutidos fatores que modulam a resposta ao estresse tais como sexo, temperamento, periodos criticos do desenvolvimento e a presenca ou ausencia de suporte social. A interacao entre os fatores geneticos e ambientais gera os perfis da resposta psicofisiologica que caracterizam os fenotipos de susceptibilidade e resiliencia frente aos estressores e sua relacao com uma patologia mental cada vez mais presente na sociedade moderna, o transtorno de estresse pos-traumatico.