Pathological aggression and antisocial behavior
Description of disorder:
Pathological aggression (PA) is a burdensome and intractable pattern of violent and disruptive conduct caused by complex gene x environment (GxE)
interactions. One of the key challenges in PA treatment stems from the heterogeneity of its two main constructs 1) reactive, which is enacted impulsively in response to a perceived threat; and 2) proactive, which is premeditated and goal-or reward- driven. Although these two constructs are markedly distinct, they typically concur in the same individuals and share multiple risk factors. Elucidating the neurobiological processes underlying the commonalities and divergences of reactive and proactive PA could lead to therapeutic breakthroughs; however, these mechanisms remain largely elusive. We have characterized the first mouse model of GxE interaction in PA. Specifically, we focused on the interaction between low-activity variants of the gene encoding monoamine oxidase (MAO) A and childhood maltreatment, which has been shown to increase the risk of PA in humans. We reproduced this interaction by subjecting MAO-ANeo mice (a novel MAO-A hypomorphic mouse line generated in our laboratory) to a specific early-life stress (ES) regimen capturing the effects of physical abuse and neglect. This manipulation resulted in high levels of aggression, mimicking the conditions observed in humans. We characterized that the underpinnings of these behavioral responses reflect the hyperactivation of serotonin 5-HT2A receptors in the prefrontal cortex during the first week of life. These alterations lead to progressive changes in the subunit composition of the NMDA glutamate receptors and dopaminergic response, ultimately resulting in overt functional modifications of the prefrontal cortex. Our recent findings indicate that the development of PA may follow a similar trajectory as addiction, with a progressive acquisition of dopaminergic changes in the nucleus accumbens. This progression may explain why PA leads to high recidivism, with characteristics akin to addiction relapse.
Ongoing projects:
- Study how early-life 5-HT2AR activation in the PFC dysregulates the mesolimbic dopamine system.
- Study how androgenic steroids shape aggression and dopamine transmission in ES MAO-ANeo mice.
- Determine whether ES MAO-ANeo mice are “addicted” to aggression.
- Determine the neurodevelopmental mechanisms of alcohol consumption in ES MAO-ANeo mice.
- Test how the interaction of ES and Maoa genotypes modulates the pro-aggressive effects of alcohol.
- Delineate the effects of social challenges on alcohol reward and reinforcement.
Tourette syndrome
Description of disorder:
Tics are semi-voluntary, persistent movements or utterances that impose a severe burden on affected children. The most disabling tic disorder, Tourette Syndrome (TS), is a neurodevelopmental disorder characterized by multiple motor and at least one phonic tic for more than one year. TS prevalence is 0.5-1% in the pediatric population with a marked male preponderance. The median age of onset of TS is around 6-7 years, and tic severity increases progressively, peaking in puberty (~ 12 years old), and gradually receding afterward. TS is complicated by the fact that tic severity is influenced by environmental factors such as acute stress, and the very high prevalence of comorbid psychiatric disorders, such as obsessive-compulsive disorder (OCD), attention-deficit hyperactivity disorder (ADHD), anxiety, and depression. Current pharmacotherapies for TS remain highly unsatisfactory. The main pharmacological strategies for TS, dopaminergic antagonists and α2 adrenergic agonists4, are associated with poor efficacy and significant side effects.
We have defined vital mechanisms whereby neurosteroids play a role in symptom fluctuations in Tourette syndrome. This work, currently funded by three NINDS R21 grants, has led to the foundation of ReConNECT (Research Consortium on NeuroEndocrine Causes of Tics), the first Consortium to understand the role of steroid hormones in the pathophysiology of this disease. This line of research has already led to substantial progress toward understanding the pathophysiology of Tourette syndrome. For example, we have substantiated that acute stress leads to tic exacerbation by increasing the levels of the neuroactive steroid allopregnanolone. A clinical trial on the antagonist of allopregnanolone, isoallopregnanolone, which was informed by our results in animal models, is currently being performed in Denmark. In addition, our research is now examining the neurobiological basis of the male predominance as well as the age of onset of Tourette syndrome. Finally, we are studying how different predisposition genes lead to the ontogeny of tic disorders.
Ongoing Projects:
- To model the impact of early-life CIN depletion in mice and assess its impact on stress susceptibility
- To elucidate the role of protocadherins in TS ontogeny, validate the first models of TS based on high-risk vulnerability genes and to study their transcriptome
- To identify early phenotypes and factors that may predict the onset of TS
- To assess the role of several environmental risk factors (acute stress, inflammation and cytokines, gut microbiota, prenatal smoking, early-life stress) for TS
- To elucidate the biological mechanisms underlying the onset of tics at the age of 6-7 years
- To study sex differences in TS and the role mediated by neurosteroids
- To identify novel pharmacological tools cannabinoid-, 5-HT2A receptor-, muscarinic receptor-, α2-adrenergic receptor-based for the treatment of TS
Behavioral and drug addictions
Description of disorder:
A parallel line of research deals with the role of neurosteroids in the pathophysiology of substance use disorders and behavioral addictions. This work has led to several recent articles (published in Journal of Clinical Investigation and Behavioral Brain Bulletin) showing that the neurosteroid inhibitor finasteride blocks opioid self-administration and risk-taking behaviors. These results are in line with previous clinical observations from my group on the use of finasteride (a neurosteroid synthesis inhibitor) in pathological gambling.
Ongoing projects:
- To identify novel targets steroid-based to treat opioid use disorder
- Gambling
Sleep deprivation
Description of disorder:
Sleep represents a vital function for energy conservation and homeostasis of multiple physiological and behavioral process, and whose deprivation can be a factor of vulnerability in the development of psychiatric diseases such as anxiety, depression and psychosis. The economic repercussions of sleep deficits are staggering, due to their negative influence on public safety and work productivity. These devastating effects are known to be contributed by alterations of executive functions, a class of processes that enable the enactment of purposive, goal-directed tasks and attune cognitive and emotional responses to the environment. In particular, sleep deprivation (SD) determines alterations of the information filtering functions, regulated by a neurobiological circuit called "sensorimotor gating", which allows the brain to evaluate what is salient and fundamental and what is irrelevant and harmful. The functioning of this circuit can be measured experimentally through the diagnostic test of the Prepulse Inhibition (PPI), which is deficient in patients suffering from different psychiatric disorders. In rats SD has been shown to cause behavioral alterations such as hyperactivity, stereotyped behaviors, aggression and PPI deficits, which respond to antipsychotic drug administration. These manic-like behaviors are also associated with alterations of dopaminergic activity in the prefrontal cortex and in the nucleus accumbens, two areas of the mesocorticolimbic system that play a key role in determining the value and salience of the stimuli. Due to these characteristics, the rodent model of SD has been extensively studied as a possible animal model of mania. In the SD-induced mania model, the onset of manic-like behaviors has been frequently associated with hyperactivity of the prefrontal cortex, associated to a modified GABAergic transmission, which also could contribute to dysfunctions of the mesocorticolimbic dopaminergic system. Moreover, recent preclinical evidence suggesting that neuroactive steroids (an important class of mediators that regulate sleep and stress response) may be critical in mediating and shaping the executive function deficits associated with SD.
Ongoing projects:
- Study how BDNF and its receptor TrkB modulate neurological impairment due to lack of sleep
- Study the neurobehavioral complications of sleep deprivation and the effects of chloride homeostasis imbalances in the PFC pyramidal neurons
Depression
Description of disorder:
Among psychiatric disorders, depression has a high incidence and an elevated societal cost. Although its etiology is largely unknown, it is widely accepted that the concurrence of genetic and epigenetic factors leads to the manifestation of this illness. Among epigenetic factors, exposure to chronic stress has a prominent role in the etiology of depression. When stress occurs, it activates the hypothalamic–pituitary–adrenocortical axis and the autonomic stress system, and it also affects the chemical balance of many brain areas. Previous investigations showed that the enzyme steroid 5α-reductase 2 (5αR2) is expressed in key brain areas for emotional and socio-affective reactivity, yet the role of this enzyme in behavioral regulation remains mostly unknown. 5αR2 represents the rate limiting step for the conversion of testosterone into the potent androgen 5α-dihydrotestosterone. Moreover, 5αR2 catalyzes the conversion of progesterone and deoxycorticosterone into 5α-dihydroprogesterone and 5α-dihydrodeoxycorticosterone, that are further converted by 3α-hydroxysteroid oxidoreductase into tetrahydroprogesterone (allopregnanolone; AP), and tetrahydrodeoxycorticosterone (THDOC), respectively. In particular, the positive allosteric modulators of GABAA receptors AP and THDOC play key roles in the orchestration of reactivity to stress and other environmental stimuli as well as in the pathophysiology of depression and anxiety.
Ongoing projects:
- To study the role of 5 alpha-reductases (5αRs) in mood regulation and stress reactivity by means of knock-out (KO) animal models and knock-down approaches
- To study the impact of 5αRs in the establishment of social dominance and its behavioral manifestations
- To test the behavioral effects of the prototypical 5αR inhibitor, finasteride, in order to assess its effects on complementary aspects of mood regulation, anxiety, impulse control, and stress reactivity
- To establish and design novel methods to catch depression phenotypes in animals