Developmental plasticity and circuit mechanisms of dopamine-modulated aggression

Aggression and violence pose a significant public health concern to society. Aggression is a highly conserved behavior that shares common biological correlates across species. While aggression developed as an evolutionary adaptation to competition, its untimely and uncontrolled expression is maladaptive and presents itself in a number of neuropsychiatric disorders. A mechanistic hypothesis for pathological aggression links aberrant behavior with heightened dopamine function. However, while dopamine hyper-activity is a neural correlate of aggression, the developmental aspects and circuit level contributions of dopaminergic signaling have not been elucidated. In this dissertation, I aim to address these questions regarding the specifics of dopamine function in a murine model of aggressive behavior. In chapter I, I provide a review of the literature that describes the current state of research on aggression. I describe the background elements that lay the foundation for experimental questions and original data presented in later chapters. I introduce, in detail, published studies that describe the clinical manifestation and epidemiological spread, the dominant categories, the anatomy and physiology, and the pharmacology of aggression, with a particular emphasis on the dopaminergic system. Finally, I describe instances of genetic and environmental risk factors impacting aggression, concluding with studies revealing an important role for interactions among genetics, environmental factors, and age in the development of aggression. In chapter II, I investigate the developmental origins of aggression by examining sensitive periods during which perturbations to the dopaminergic system impact adult aggressive behavior. Previous work in our laboratory has concluded that periadolescent (postnatal days 22-41) elevation in dopamine, via transient dopamine transporter blockade, leads to increased adult aggression and heightened response to amphetamine. I expanded on these findings by temporally refining the opening and closing of this window of sensitivity, specifically to postnatal days 32 to 41, during which increases in dopaminergic tone increase adult aggression and behavioral sensitivity to psychostimulants. The potentiated response to amphetamine indicated to us a state of altered dopaminergic physiology. We next validated this hypothesis and found increased firing rate (in vitro), and increased bursting and population activity (in vivo) at baseline. These data indicate that elevated periadolescent dopamine impacts maturation of the dopamine system, leading to a hyper-active dopaminergic and aggressive predisposition. In conclusion, this chapter introduces a developmental component to the hyper-dopaminergic model of aggression. In chapter III, I report a series of experiments exploring the direct and causal involvement of dopamine in driving aggression. While dopamine hyper-activity is a neural correlate of aggression, the precise brain circuits involved have not been elucidated. Using optogenetics, I established a causal role for the ventral tegmental area (a key source of dopamine) in aggression modulation. I further advanced this finding by demonstrating that the modulatory role of dopamine, is population- and projection-specific. I found that activity of ventral tegmental area, but not substantia nigra, dopamine neurons promotes aggression. Furthermore, controlled stimulation of ventral tegmental area dopaminergic terminals in the lateral septum, but not the nucleus accumbens, mediates increased aggression. I selectively traced connectivity between the lateral septum and the ventral tegmental area using a Cre-driven, population-specific viral vector. I used this virus to show that anatomically distinct clusters of ventral tegmental area dopamine cells send projections to the lateral septum and the nucleus accumbens, thereby dissociating the two target sites both behaviorally and anatomically. Furthermore, I found that while local dopamine release in the lateral septum increases aggression, it has no bearing on reward behaviors thus indicating a stronger association with impulsive, and not motivated, aggression. In conclusion, this chapter offers causal evidence for dopamine’s role in modulating impulsive aggression by identifying a distinct pathway from the ventral tegmental area to the lateral septum that controls aggression. In the work described in chapter IV, my aim was to determine the mechanism underlying ventral tegmental area to lateral septum dopamine-mediated aggression. I first characterized the expression of dopamine receptors in the lateral septum and found that D2 receptors heavily colocalize with the dominant population of neurons in the lateral septum, i.e. GABAergic cells. Moreover, the D2 receptors are perfectly aligned with incoming dopamine afferents. Next we investigated, in acute brain slices, how D2 signaling affects lateral septum function. We revealed that activating D2 receptors hyperpolarizes D2-expressing lateral septum neurons. This effect was abolished with bath application of the D2 receptor antagonist, sulpiride. We validated the functional involvement of post-synaptic D2 signaling in a behavioral test, and found that the aggression induced by direct terminal release of dopamine at the lateral septum is reversed by acutely blocking local D2 receptor signaling. In conclusion, this chapter demonstrates that the ventral tegmental area to lateral septum dopamine pathway, via D2-mediated inhibition of GABAergic lateral septum neurons, is necessary to drive ventral tegmental area-triggered aggression. In chapter V, I engage in a general discussion addressing how the findings from each chapter can be linked to provide a more comprehensive outlook on environmental and genetic risk factors that can modulate ventral tegmental area-triggered aggression. I discuss possible pre- and post-synaptic mechanisms that could impact the functionality of the identified dopaminergic ventral tegmental area to lateral septum pathway. Moreover, in distinguishing this specific dopamine circuit and lateral septum D2 signaling as an underlying correlate of violent pathology, this dissertation aims to evoke deeper understanding of the mechanism of current antipsychotics used to manage aggression. I end this dissertation by proposing new empirical questions, techniques and lines of research that could further develop my findings as well strengthen the links between dominant models of aggression that exist in the field today

Introduction. Safe and inclusive cities: contesting violence

Introduction. Safe and inclusive cities: contesting violenc

Women’s Safety and Public Spaces: Lessons from the Sabarmati Riverfront, India

The Sustainable Development Goals 5 and 11, as well as the New Urban Agenda, emphasize gender equity and safe, resilient, and inclusive cities. The ‘safe cities’ idea for women includes their equal right to the city and public places within it, which includes their right to be mobile in the city at any time of the day, as well as their right to loiter in public spaces without any threats of harassment or sexual violence. These issues have gained importance in urban planning and design in contemporary India. This article is an assessment of how safe Ahmedabad city’s largest public space, the Sabarmati Riverfront, is for women. Ahmedabad, a city in western India, has long carried an image of a safe city for women. The Sabarmati Riverfront is over 22 km in length, 11 km on both sides of the river. This assessment is made through mapping of space use disaggregated by sex and age at four different time points throughout the day and of 100 women’s accounts of the experience of harassment on using the space. The article concludes with specific recommendations on proposed activities and space design along the riverfront to make these spaces safe for women throughout the day

City profile : Guwahati

This paper lays out relevant urban context in terms of demography, economic history and employment, the history of migration and conflicts in Assam and Guwahati, the processes of urban growth and development in the city, as well as urban governance. Part II identifies and discusses key arenas of conflicts and violence that are linked to land, planning and governance regimes in the city, namely, informal settlement of the city’s hills, street vending, and women’s safety and safe access to public transport. These arenas of conflict and violence are the focus areas for the research project

City profile : Ahmedabad

This research investigates potential pathways through which urban planning and governance mechanisms become drivers of deprivations, conflicts and violence. While also developing a background understanding of Ahmedabad, it discusses contexts of demography and economic transformations since liberalization; their impacts for urban poverty and inequality; the historical growth of the city and resulting spatial segmentation; the current status of housing amongst urban poor and low-income groups; and the urban development paradigm in terms of planning, housing, basic services, street vending and public transport. How can urban planning and governance interventions help reduce urban tensions, inequalities, conflicts and violence in Indian cities

Tenure Security and Urban Social Protection Links: India

Guaranteeing tenure security to the households living in informal settlements (slums) has not seen any progress in urban India. This is because the policymakers have failed to see land tenure status as a continuum from insecure tenure to a legal status. In general, the poor in the cities move from informal to quasi?legal ( de facto ) tenure through various processes, and then to legal tenure ( de jure ) in cases of a public policy intervention that confers property title on them. In the absence of such a policy, the urban poor and low?income migrants can seek to consolidate their urban citizenship through political citizenship in an electoral democracy, through welfare interventions by the state and above all, through their own subversions of urban legalities. This article first illustrates the existence of a continuum of tenure status in informal settlements in Ahmedabad City. It explains the factors that give a slum settlement a particular level of tenure status; and then through quantitative data, links the level of tenure security to social protection outcomes. The article shows that through small public actions, it is possible to improve access of the urban poor to social protection measures and that it is not necessary to leapfrog to extending property rights to the dwellers of these informal settlements. It is essential to realise that if land titles are given in a society where other rights are not present, the poor will not be able to retain them