Adolescence is a sensitive developmental period encompassing neural maturation that is critical for an individual’s behavioral transition into adulthood. Due to widespread physiological changes attributed to this period, adolescents are also vulnerable to the initiation of risky behaviors, such as drug experimentation and use, as well as the emergence of various neuropsychiatric disorders. The mesocorticolimbic dopamine (DA) system in the brain undergoes a transient peak in activity and continues to mature during adolescence, potentially mediating adolescent hypersensitivity to social, appetitive, and drug-associated rewards. Simultaneously, the serotonin (5-HT) system exerts its influence on the dopamine system throughout adolescence, a process vital for proper impulse control and emotional regulation in adulthood. Substance use disorders (SUDs) are multifaceted and are comprised of diverse maladaptive behaviors that promote compulsive drug seeking, including loss of control and the propensity to engage in drug use irrespective of personal risks and/or consequences. Drug addiction and substance use have a large negative impact globally both economically and with regards to public health outcomes, representing approximately 1.3% of the global burden of disease. Furthermore, dopamine reward pathways are heavily impacted by drug use, particularly with respect to stimulants, and the level of drug-induced dopamine release in the ventral striatum can be correlated with a drug’s perceived “high.” Certain experiences and adverse behaviors linked to refinement of monoamine connectivity in the brain during adolescence, such as heightened stress and sensation seeking, may predispose individuals for developing SUDs in adulthood. However, how drug reward sensitivity and associated activity of the dopamine system is altered in adulthood as a consequence of interfering with monoamine neurodevelopment during adolescence has not been clarified. To this end, I aim to understand how imbalanced monoamine development during adolescence contributes to stimulant-mediated behaviors in adulthood, specifically contextual reward associations, in relation to in vivo activity of the dopamine reward system. I introduce a sensitive peri-adolescent (PA) period in mice, during which blockade of the serotonin transporter (SERT) via fluoxetine administration during postnatal (P) days 22-41 leads to inhibited adult aggression and locomotor response to stimulants. Conversely, I describe a more refined PA (P32-41) period during which systemic dopamine transporter (DAT) blockade via GBR12909 administration leads to enhanced aggression and stimulant-induced locomotor activity in adulthood. Utilizing these behaviorally opposing models characterized in our lab, I describe the diverging effects of systemic DAT and SERT blockade from P32-41 on cocaine-induced locomotor response as well as cocaine-mediated contextual preference. I administered cocaine intraperitoneally (i.p.) at doses of 5 and 10 mg/kg, applying the open field test and cocaine conditioned place preference (CPP) paradigm to assess stimulant-induced locomotor response and environmental reward associations, respectively. Potentiation of serotonergic tone during P32-41 via fluoxetine administration leads to decreased cocaine-induced locomotor response and a lack of preference for a cocaine-associated context in adulthood at a dose of 10 mg/kg, compared to controls and PA GBR treated subjects. Conversely, potentiation of dopaminergic tone by administering GBR12909 during P32-41 is associated with enhanced cocaine-induced locomotor reactivity at 10 mg/kg and greater contextual preference at lower doses of cocaine (5 mg/kg), in comparison to PA fluoxetine treated mice and controls. To understand how in vivo VTA dopamine population activity is altered in both PA models during cocaine-associated behaviors in adulthood, I performed cocaine CPP while recording calcium signals in VTA dopamine neurons using fiber photometry in freely behaving subjects. Importantly, I utilize these recordings as a proxy for measuring changes in VTA dopamine activity as the subjects engage with a cocaine-paired environment. I found that PA DAT blockade was associated with greater baseline VTA dopamine activity in adulthood compared to controls, as well as heightened VTA dopamine activity while the subjects were in a cocaine-paired context during selected portions of the behavioral task compared to control subjects. Additionally, we found a significant positive correlation between the magnitude of preference for a cocaine-associated context and the frequency of VTA dopamine calcium signals recorded while the subject is engaged with a cocaine-paired environment. Adult mice following PA DAT blockade displayed a greater frequency of recorded VTA dopamine calcium signals while in a cocaine-paired environment compared to PA fluoxetine treated mice. Supporting our correlational analysis, I detected a decreased preference for a cocaine-paired context in PA fluoxetine treated subjects compared to both controls and PA GBR12909 mice, when using a dose of cocaine in between the previous concentrations tested (7.5 mg/kg). Interestingly, PA fluoxetine treated subjects showed transition-dependent differences in VTA dopamine calcium activity during the final five-minute portion of our behavioral task, displaying less activity shortly post-entry into the cocaine-paired environment compared to pre-entry. In congruence, PA fluoxetine subjects showed enhanced VTA dopamine calcium activity on the saline-paired side shortly post-entry compared to pre-entry. In collaboration with the Sulzer Lab, we also probed the effects of both PA manipulations on electrically evoked dopamine release in the ventral striatum of adult anesthetized mice using fast-scan cyclic voltammetry. Electrical stimulation was targeted to the midbrain and evoked dopamine release was recorded in the ventral striatum both at baseline and in response to cocaine injection, using the same 7.5 mg/kg dose applied in the calcium imaging study. Overall, we found a significant increase in dopamine release at baseline in the ventral striatum of adult PA GBR12909 treated subjects compared to both PA fluoxetine subjects and controls. Moreover, we found significantly greater cocaine-induced dopamine release in our PA GBR12909 mice compared to controls in adulthood. These findings are consistent with the imaging and behavioral data, highlighting the persistence of an elevated dopaminergic phenotype due to systemic PA DAT blockade. Conversely, systemic PA SERT blockade leads to behaviorally opposing effects and generally lower VTA DA activity dynamics in comparison to PA GBR12909 treated subjects in adulthood. The unique, combinatorial approach applied in this dissertation work further our knowledge of how sensitive developmental periods influence the emergence of complex behaviors in adulthood, which is vital to improving treatment approaches for neuropsychiatric disorders.

Introdução: O transtorno bipolar (TB) é um problema crônico, de evolução cíclica, altamente prevalente na população geral e está associado a importante incapacitação dos pacientes e a déficits cognitivos e funcionais, constituindo, assim, um importante problema de saúde pública. A etiologia do TB parece ser multifatorial, resultante da interação entre fatores genéticos e ambientais; estudos apontam que a predisposição para manifestação de episódios pode advir da exposição a maus-tratos na infância (MTI), que comprometem o desenvolvimento emocional, cerebral e cognitivo das crianças e estão presentes em 30% a 60% dos portadores de TB. No TB, os MTI vem sendo associados com idade de início mais precoce, pior evolução clínica, maior incidência de comorbidades, apesar da literatura ser escassa e não conclusiva, tem sido associado também a alterações do funcionamento cognitivo e da morfologia cerebral. Objetivo: Investigar se o perfil cognitivo e a morfometria cerebral de portadores de TBI eutímicos diferencia-se com a exposição ou não a maus-tratos sofridos na infância. Método: 75 portadores de TBI eutímicos, com idades entre 18 e 45 anos, atendidos no ambulatório do Programa de Transtornos Afetivos (GRUDA) IPq-HC-FMUSP, sendo 32 sem história de MTI e 43 com história de MTI, de acordo com o ponto de corte do Childhood Trauma Questionnaire (CTQ) e 46 voluntários sadios do ponto de vista físico e mental, com idades entre 18 e 45 anos, sem história de MTI de acordo com o CTQ e sem parentes de primeiro grau com transtornos psiquiátricos foram submetidos a uma bateria de testes neuropsicológicos que avaliou as funções atencionais, mnêmicas, executivas e cognição social e a um estudo de imagem por ressonância magnética. Resultados: Os resultados apontaram para uma diferença de desempenho cognitivo entre os grupos em uma das medidas de flexibilidade mental (p=0,04), em uma de raciocínio matricial (p=0,035) e na capacidade de reconhecimento de emoções faciais de tristeza (REF, p=0,022). Em relação à morfometria cerebral, pôde-se observar que o volume do Núcleo Caudado apresentou diferença estatisticamente significativa entre os três grupos, tanto no hemisfério direito (p=0,002) como no esquerdo (0,008). No hemisfério esquerdo, a área do Órbito Frontal Medial (p=0,0466), a área do Pré-cuneo (p=0,0193) e a área do Parietal Superior (p=0,0063) apresentaram diferenças estatisticamente significativas. No hemisfério direito, a área do Órbito Frontal Medial (p=0,0200), a área do Pré-cuneo (p=0,0337), a área do Parietal Superior (p=0,0007), a espessura da Parte Triangular do Córtex Frontal (p=0,0013), a espessura do Pré-central (p=0,0307) e a espessura do Frontal Superior (p=0,0425) apresentaram diferenças estatisticamente significativas. Por fim, a partir de uma análise exploratória, pôde-se observar que no grupo de portadores de TB com MTI os resultados apontam para possíveis associações entre regiões cerebrais e desempenhos cognitivos, sendo elas: volume do Hipocampo Direito e o TMT-B (pinteração= 0,002, r = -0,40, pr=0,013), área do Giro Superior Frontal Direito e o SCWT-I (pinteração= 0,0008, r = -0,36, pr=0,0185), área do Órbito Frontal Medial Esquerdo e o FCR-cópia (pinteração= 0,004, r = 0,49, pr=0,014), espessura do Órbito Frontal Medial Direito e COWAT-total (pinteração= 0,004, r = 0,46, pr=0,003), espessura do Frontal Medial Rostral Esquerdo e WCST-erros (pinteração= 0,007, r = -0,42, pr=0,007). Conclusões: Apesar da limitação do tamanho amostral e do número de comparações estatísticas realizadas, este é o primeiro estudo a avaliar a associação entre MTI, funcionamento cognitivo e morfometria cerebral. Os resultados foram sugestivos de que a magnitude das correlações entre as características morfométricas e cognitivas podem ser moduladas pela exposição a MTI e pelo status de caso (portador de TB) / Introduction: Bipolar disorder (BD) is a chronic, cyclically-evolving problem that is highly prevalent in the general population and is associated with significant disability of the patients and cognitive and functional deficits, thus constituting an important public health problem. The etiology of BD seems to be multifactorial, resulting from the interaction between genetic and environmental factors, and studies show that the predisposition to the manifestation of episodes of BD may result from exposure to childhood maltreatment (CM), which compromises the emotional, cerebral and cognitive development and seems to be present in between 30 and 60% of BD patients. In BD, CM have been associated with earlier onset age, worse clinical course, higher incidence of comorbidities and, although the literature is scarce and not conclusive, it has also been associated with changes in cognitive function and brain morphology. Objective: To investigate whether the cognitive profile and the brain morphometry of patients with euthymic BD differ between those exposed or non-exposed to CM. Method: 75 euthymic BD patients, aged between 18 and 45 years, attended at the ambulatory of the Affective Disorders Program (GRUDA) IPq-HC-FMUSP, 32 of which had no history of CM and 43 with a positive history of CM according to the cut-off of the Childhood Trauma Questionnaire (CTQ) and 46 physically and mentally healthy volunteers, aged 18-45 years, with no history of CM according to the CTQ and no first-degree relatives with psychiatric disorders were submitted to a battery of neuropsychological tests that evaluated attentional, mnemonic, executive, and social cognition functions and a study of magnetic resonance imaging. Results: The results point to a difference in cognitive performance between groups in one of the measures of mental flexibility (p = 0.04), in one of matrix reasoning (p = 0.035) and in the ability to recognize facial emotions of sadness FER, p = 0.022). Regarding cerebral morphometry, it can be observed that the volume of the Caudate Nucleus showed a statistically significant difference between the three groups, both in the right hemisphere (p = 0.002) and in the left hemisphere (0.008). In the left hemisphere, the area of Medial Orbital Frontal (p = 0.0466), the area of Precuneus (p = 0.0193) and the area of Superior Parietal (p = 0.0063) presented statistically significant differences. In the right temisphere, the area of Medial Orbital Frontal (p = 0.0200), the area of Precuneus (p = 0.0337), the area of Superior Parietal (p = 0.0007), the thickness of Pars Triangularis (p = 0.0013), the thickness of Precentral (p = 0.0307) and the thickness of Superior Frontal (p = 0.0425) presented statistically significant differences. Finally, from this exploratory analysis, it is possible to observe that in the group of BD with CM the results point to possible associations between brain regions and cognitive performance, specifically: Right Hippocampus Volume and TMT-B (pinteraction = 0,002, r = -0,40, pr=0,013), Right Superior Frontal Area and SCWT-I (pinteraction = 0.0008, r = -0.36, pr = 0.0185), Left Medial Orbital Frontal area and FCR-copy (pinteraction= 0,004, r = 0,49, pr=0,014), Right Medial Orbital Frontal Thickness and COWAT-total (pinteraction = 0.004, r = 0.46, pr= 0.003), Left Rostral Medial Frontal Thickness and WCST-errors (pinteraction = 0.007, r = -0.42, pr = 0.007). Conclusions: Despite the limitation of the sample size and the number of statistical comparisons performed, this is the first study to evaluate the association between CM, cognitive functioning and brain morphometry. The results are suggestive of the magnitude of the correlations between the characteristics morphometric and cognitive variables can be modulated by exposure to CM and by case status (BD patients)

No description available.

In order to assess flexibility in acquiring and using conflicting response rules, rats with selective lesions of the NBM or sham-lesion controls were subjected to serial reversal training in a simple operant discrimination paradigm. The NBM lesion group did not differ from the control group in acquisition of the original rules; the NBM lesion group required more time to master the changes in rules in the first reversal, but not in subsequent reversals.

A perimenopausa é a fase da vida reprodutiva feminina caracterizada diversas alterações, inclusive cognitivas devido ao hipoestrogenismo. Através de estudo duplo-cego randomizado com 16 mulheres na perimenopausa deprimidas que receberam estradiol e 16 que receberam placebo analisou-se as alterações cognitivas da atenção, memória e linguagem; o efeito da reposição hormonal com estradiol e a correlação entre os sintomas depressivos e menopausais com as alterações destas funções. Os resultados mostraram: melhora do controle inibitório, memória imediata e tardia (verbal e visual) e da capacidade de nomeação nos dois grupos; melhora dos sintomas depressivos e menopausais para o grupo que recebeu reposição hormonal: e não correlação entre a melhora destes sintomas e a melhora das funções cognitivas / Perimenopause is the female reproductive life period characterized by several changes including cognitive impairments related to hypoestrogenism. In a randomized double-blind study 16 depressive perimenopaused women took estradiol, while another group of 16 depressive perimenopaused women took placebo. Cognitive alterations associated to attention, memory and language, and estradiol hormone replacement therapy effects were evaluated. In addition, correlations among symptoms of depression and menopause, and cognitive alterations were also analyzed. The results had shown, in both groups, an improvement in inhibitory mental control, in immediate and delayed (verbal and visual) memory, and in naming capacity. In the group that received hormone replacement therapy our findings revealed a weakening of depression and menopause symptoms, which had shown no correlation with cognitive functions

A perimenopausa é a fase da vida reprodutiva feminina caracterizada diversas alterações, inclusive cognitivas devido ao hipoestrogenismo. Através de estudo duplo-cego randomizado com 16 mulheres na perimenopausa deprimidas que receberam estradiol e 16 que receberam placebo analisou-se as alterações cognitivas da atenção, memória e linguagem; o efeito da reposição hormonal com estradiol e a correlação entre os sintomas depressivos e menopausais com as alterações destas funções. Os resultados mostraram: melhora do controle inibitório, memória imediata e tardia (verbal e visual) e da capacidade de nomeação nos dois grupos; melhora dos sintomas depressivos e menopausais para o grupo que recebeu reposição hormonal: e não correlação entre a melhora destes sintomas e a melhora das funções cognitivas / Perimenopause is the female reproductive life period characterized by several changes including cognitive impairments related to hypoestrogenism. In a randomized double-blind study 16 depressive perimenopaused women took estradiol, while another group of 16 depressive perimenopaused women took placebo. Cognitive alterations associated to attention, memory and language, and estradiol hormone replacement therapy effects were evaluated. In addition, correlations among symptoms of depression and menopause, and cognitive alterations were also analyzed. The results had shown, in both groups, an improvement in inhibitory mental control, in immediate and delayed (verbal and visual) memory, and in naming capacity. In the group that received hormone replacement therapy our findings revealed a weakening of depression and menopause symptoms, which had shown no correlation with cognitive functions