AGGRESSION, STRESS and DEPRESSION

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1 AGGRESSION, STRESS and DEPRESSION Bi156 Jan. 18, 2012 Paul Patterson

2 Anatomy of aggression Aggressive behavior presumably evolved for useful purposes. Aggression can be defensive or offensive towards other members of the same species (access to mates, food), towards members of other species (predation), or towards oneself (suicide). Different pathways mediate the various forms of aggression. Attacks can be evoked by electrical stimulation of the amygdala, hypothalamus or the periaqueductal gray (PAG). In cats, stimulation of the amygdala or medial hypothalamus can elicit attacks on other cats, via the PAG. Stimulation of the lateral hypothalamus elicits predation, via the ventral tegmental area. Electrical stimulation of the ventromedial nucleus of the hypothalamus in rats provokes aggression, as does optogenetic activation of this area in mice. Premeditated ( controlled-instrumental ) aggression (intimidation, assassination) is presumably regulated by higher cortical systems and less dependent on the hypothalamic and limbic systems.

Rodent Primate Lesions in LAS (septum), BNST (stria terminalis), AHA (anterior hypothalamus) or MEA (amygdala) reduce aggression between male rats, and reduce vocal threats in monkeys.

3 Rodent Primate Lesions in LAS (septum), BNST (stria terminalis), AHA (anterior hypothalamus) or MEA (amygdala) reduce aggression between male rats, and reduce vocal threats in monkeys. Genetic silencing of the ventromedial hypothalamus (VMH) in mice inhibits natural aggression. Lesions in OFC (cortex) or POA (preoptic) increase aggression in male rats, and in dominant but not subordinant male monkeys (interpretation of social cues). Conversely, electrical stimulation of the VMH increases aggression in rats, and stimulation of the VMH, AHA, BNST or POA (preoptic area) increases vocal threats in male marmosets and monkeys. Optogenetic stimulation activation of the VMH in mice elicits attacks. c-fos (immediate early gene) expression is increased in the LAS, BNST, AHA and MEA during aggression in rats. In humans, damage to prefrontal cortex (PFC) is associated with aggressive behavior, and people with lower than average basal activity there rank highly on tests of reactive aggression. Elevated activity in the amygdala is correlated with lifetime aggression scores. Nelson & Trainor, 2007

4 Serotonin functions Murphy et al., 2008

5 Serotonin circuits

6 Role of serotonin (5-HT) in violent behavior Human studies have correlated lowered activity in the 5-HT system with impulsive (not premeditated) aggressive and suicidal behavior. History of suicidal behavior correlates inversely with levels of the 5-HT metabolite 5-HIAA in the CSF. Similar correlations with 5-HIAA with impulsive arson, psychopathic deviance and life history of aggression. Selective serotonin reuptake inhibitors (SSRIs) reduce aggression scores and increase baseline activity in prefrontal cortex (PFC). Position in the social hierarchy of non-human primates predicts 5-HIAA levels. In general, lowering 5-HT activity (receptor blockers or KO) in rodents increases aggressive responses, while raising 5-HT activity (increasing tryptophan, SSRIs, receptor agonists) decreases aggressive responses.

7 5-HT & aggression in primates Lower 5-HT metabolite is correlated with increased aggression and risk taking. b = p<.05 Mehlman et al., 94

8 5-HT receptors and behavior * * * Gaspar, 03

9 5-HT receptor distribution Buhot, 97

10 Phenotypes of various KOs in the 5-HT system * * Gingrich & Hen, 01

11 Enhanced aggression in 5-HTR 1B KO mice Resident-intruder aggression test. Mice were WT (open bars), heterozygote (gray bars), or null (black bars) for the 5-HT receptor. (A) Attack latency: time between the introduction of the intruder and the first attack by the resident. (B) Number of attacks. Saudou et al., 94

12 Vasopressin - 5-HT interactions Next week we will discuss how vasopressin (AVP) regulates defensive aggression in male voles via its AVP1 receptor. There is an interaction between AVP and 5-HT in the anterior hypothalamus; 5-HT synapses are observed on VP neurons. The selective 5-HT reuptake inhibitor (SSRI) fluoxetine (Prozac) lowers aggression in hamsters in the resident/intruder paradigm. Conversely, AVP injection into this part of the hypothalamus increases aggression. This action of AVP is blocked by prior injection of fluoxetine.

13 5-HT and AVP circuits in aggression Ferris et al., 97

14 Blocking 5-HT uptake diminishes biting Ferris et al., 98

15 5-HT diminishes biting by suppressing AVP effects Ferris et al., 97

16 Social subjugation Adolescent hamsters exposed to aggressive adults display contextdependent alteration in their aggressive behavior. Subjugated animals are more likely to attack younger and weaker intruders than are normal animals. Conversely, subjugated animals are less likely to attack animals of similar size and age than are normal animals. Subjugation decreases AVP in the anterior hypothalamus, while the number of 5-HT synapses is higher in this area. Thus, this form of stress during puberty permanently alters these brain systems in behaviorally relevant ways.

17 Aggression toward younger and smaller intruders Delville et al., 98

18 Aggression toward intruders of equal size & age Delville et al., 98

19 AVP in hypothalamus of subjugated animals Delville et al., 98

20 Monoamine oxidase and aggression Twin and adoption studies support a role for both environmental and genetic factors in human violence. Study of a large Dutch family, in which a number of males exhibit impulsive aggression and attempted murder, arson and rape, revealed abnormal levels of monoamine metabolites in the urine. Cultured skin fibroblasts from affected men lack monoamine oxidase A (MAOA). MAO is critical for breakdown of catecholamines and 5-HT. MAOA KO mice display enhanced aggression, and these behaviors are corrected by injection of a 5-HT synthesis inhibitor (but not by a catecholamine synthesis inhibitor). It is surprising that elevated 5-HT stimulates aggression, as prior studies linked deficits to aggression. In fact, MAO inhibitors do not stimulate aggression in adult humans or rodents. Thus, the current hypothesis is that the behavioral phenotype in the mutant mice (and humans?) is due to compensatory changes during brain development.

21 MAOA mutation and aggression MAO activity in cultured skin fibroblasts Brunner et al., 93

22 Aggression in MAOA knockout mice Behavioral alterations in MAOA knockout (Tg8) and controls (C3H). (A) righting response. Pups were separated from their dam, isolated for 3 min, and placed on their backs. (B) Aggression between Tg8 male cage mates. Plot represents a 1 day survey of skin wounds in 2 to 7 mo old males housed in groups. In the controls (C3H), no wounds were found. No wounds were found in female mutants. (C) Latency to first biting attack in resident-intruder test. (D) Latency to first biting attack in resident-intruder test after a period of isolation. Cases et al., 95

23 MAO and aggression There is wide variation in MAO activity in the normal human population. An upstream repeat length polymorphism contains 4 alleles that cause 2- to 10-fold differences in MAO expression. Men with high transcription alleles show reduced 5-HT responsivity and score higher on aggression and impulsivity tests. Boys with these alleles are identified by teachers and parents as being persistently aggressive. Thus, both complete absence of MAOA activity (in humans and mice) and increased MAOA activity within the normal range (in humans) are associated with increased aggressive behavior.

24 Other transmitters and aggression Aggressive behavior requires mesocorticolimbic dopamine neurons. The D 2 dopamine receptor blocker haloperidol has been used to treat aggression, especially those patients who are psychotic. D 1 and D 2 receptor blockers reduce aggression in mice. Male mice lacking the long form of the D 2 receptor, D 2 L, show reduced aggression. However, knocking out the dopamine transporter, DAT, increases dopamine levels and reduces D 1 and D 2 expression, but increases aggression. Are there different effects on aggression during development and in adults? Drug manipulations that increase GABA activity in the septal forebrain increase aggression in rodents, and levels of glutamic acid decarboxylase (GAD) are low in rodents that have recently engaged in aggressive behavior. Modulators of GABA B receptors (i.e., benzodiazapines) influence aggression, as does alcohol, which enhances GABA-mediated Cl flux.

25 Steroids and aggression Castration reduces male aggression in many, but not all, species. Testosterone can increase aggressive behavior in mice, acting at the level of the LAS, amygdala and dorsal raphe nucleus. Mutant mice lacking an active androgen receptor are not aggressive. KO of the estrogen receptor (ER ) reduces aggression in male mice. Aggression is positively correlated with the number of ER cells in the LAS, BNST and AHA.

26 Stress and corticosteroids The highest concentration of glucocorticoid (GC) receptors in the brain is in the hippocampus. GCs feedback through the hippocampus to down-regulate periventricular nucleus (PVN) and hypothalamic-pituitary-adrenal (HPA) axis activity. The hippocampus is important in verbal and spatial memory and increased GC levels induced by acute stress can impair short term memory formation. This effect is reversible. Repeated stress causes the atrophy of the dendrites of CA3 neurons in the hippocampus. This effect is mediated by GC and excitatory amino acid transmitters. If stress persists for extended periods, hippocampal neurons can die. MRI of patients with post-traumatic stress disorder (PTSD) has revealed such atrophy. Stress during early development can reset the level of responsiveness of the HPA axis, leading to over-reaction in adulthood. Stress in adulthood can inhibit the production of new granule neurons in the hippocampus.

27 Hypothalamic-Pituitary-Adrenal axis E. Hsiao

28 Major depression Diagnosis of major depressive disorder requires disturbances in sleep, appetite or sexual desire; loss of ability to experience pleasure in work or with friends (anhedonia); crying; suicidal thoughts; slowing of speech and action. Symptoms must last for minimum of 2 weeks and interfere with work and family relations. Depression is a heterogeneous disorder with a highly variable course, and a variable response to treatment. Lifetime incidence is 20% in women and 12% in men. A history of mania defines a distinct illness: bipolar disorder. Major depression is likely a result of environmental influences on genetically predisposed individuals. Multiple genes are likely involved, but remain to be firmly identified. One environmental risk factor is adverse life events, particularly in childhood.

29 HPA axis and major depression In rats, early periods of separation from the mother yields adult offspring with exaggerated stress response, elevated corticotropin releasing hormone (CRH), reduced 5-HT receptor expression and impaired DA transmission. These offspring also show signs of depression and anxiety: decreased consumption of sucrose (anhedonia), give up earlier in the forced swim test, less time in the open arm of elevated plus maze, increased startle response, and marked preference for ethanol and cocaine. Chronic administration of antidepressants (SSRIs) to adult rats who were maternally deprived as pups reverses the state of elevated ACTH, GC, CRH and anxiety behaviors, and SSRIs restore the preference for sucrose and reverse the preference for ethanol. One genetic polymorphism of interest is in the 5-HT transporter (SERT). The short allele results in a deficit in 5-HT expression and uptake. Persons with the short form and exposure to early stressful life events have greater vulnerability to depression. Stress activates the HPA axis, increasing corticosteroids and CRH, and depression is associated with increased CRH in the CSF and increased CRH expression in the PVN.

30 Belmaker & Agam, 2008

31 HPA response in adult women who experienced childhood sexual or physical abuse ACTH and cortisol changes in response to Trier social stress test (public speaking and mental arithmetic test in front of an audience). Increased HPA responses are seen in both non-depressed (ELS/non-MDD) and depressed women with history of childhood abuse (ELS/MDD), but not in controls or depressed women without a history of abuse (non-els/mdd). Notably, 85% of ELS/MDD group met criteria for post traumatic stress disorder (PTSD) compared with 36% in ELS/non-MDD group. Nemeroff, 2005

32 Short SERT allele in association with history of stressful life events predisposes to depression Caspi et al., 2003

33 Mechanism of SSRI effect on mood? SSRI treatment very quickly blocks the SERT and increases 5-HT levels. However, mood elevation in MDD does not occur for approximately 7-14 days. The same is true for anti-depressant effects of SSRIs in mice. It is likely that the effects of SSRIs on mood do involve SERT, as SERT KO mice do not display the anti-depressant effects on behavior when treated with SSRIs. Chronic SSRI treatment in mice causes a robust, time-dependent downregulation of SERT. KO of SERT causes a decrease of 5HT1A in the raphe and an increase in the hippocampus. There is also a functional desensitization of this autoreceptor (presynaptic receptor). Thus, it is possible that the key effect of SSRIs is on the level of the 5HT receptor rather than, or in addition to, the effect on SERT. SSRIs also alter levels of BDNF and neurogenesis, so these are other possible downstream, time-dependent targets. Unlike drugs acting on SERT, 5-HT4 receptor agonists exert antidepressant activity in rats within 3 days.

34 Neurogenesis and mood Anti-depressant drugs increase neurogenesis over the same time course as behavioral improvement in rodent models. Anti-depressant drugs require adult neurogenesis to decrease depression-like behaviors in rodents.

Genetic KO of neurogenesis increases depressionlike behaviors Confocal photographs of dentate gyrus doublecortin (DCX) immunostaining in mice

Neurogenesis-deficient v-tk mice showed reduced preference for sucrose in an acute test, compared with v- WT mice, under both control and

35 Genetic KO of neurogenesis increases depressionlike behaviors Confocal photographs of dentate gyrus doublecortin (DCX) immunostaining in mice treated with valganciclovir (v-wt and v-tk) for 4 weeks. DCX1 young neurons are abundant in v-wt mice but absent in v-tk mice. Neurogenesis-deficient v-tk mice showed reduced preference for sucrose in an acute test, compared with v- WT mice, under both control and restraint conditions (genotype effect F1, , P,0.01; stress effect F1,2053.1, P50.09; genotype3stress interaction F1,2050.2, P50.7; n54 8 per group). Snyder et al., 2011

36 Gender differences in 5-HT system PET imaging shows 5-HT synthesis in normal males is 52% higher than in normal females. This is done by monitoring incorporation of radioactive methyl-tryptophan into methyl-5-ht, which accumulates in serotonergic neurons. [total 5-HT is not different between males and females] This could possibly explain the finding that female rats adapt less readily than males to stress in a rodent model of depression, and that 5-HT may be involved. Healthy women are more susceptible than men to mood lowering caused by acute tryptophan depletion.

37 PET analysis of 5-HT synthesis Nishizawa et al., 97

38 Neurotrophic factor modulation of 5-HT neurons Conditional KO of brain-derived neurotrophic factor (BDNF) in the CA1 or dentate gyrus regions of the hippocampus results in normal baseline depression-like behavior but attenuated responses to SSRIs. Conversely, infusion of BDNF protein into the wild type hippocampus produces anti-depressant like effects. In humans, a common SNP in the BDNF gene (Met for Val in codon 66) is associated with alterations in memory. When this SNP is knocked into the mouse BDNF gene, the changes in human behavior are reproduced in the mouse. Moreover, these mice display enhanced anxiety in stressful environments, which is not fully normalized by fluoxetine. Thus, BDNF may play a key role in genetic predisposition to anxiety as well as in responses to SSRIs. There are also sex differences: male conditional BDNF KO mice exhibit normal depression-like behavior while females display a striking increase in this behavior.

39 Belmaker & Agam, 2008

40 References Background: * Nelson RJ and Trainor BC (2007) Neural mechanisms of aggression. Nature Rev Neurosci 2: * Belmaker RH, Agam G (2008) Major depressive disorder. New Eng J Med 358: Patterson PH (2011) Infectious Behavior: Brain-Immune Connections in Autism, Schizophrenia and Depression, MIT Press, Cambridge, MA, 162 pp. Student papers: * Bartal IB, Decety J, Mason P (2011) Empathy and pro-social behavior in rats. Science 334: * Schwandt ML, Lindell SG, Sjoberg RL, Chisholm KL, Higley JD, Suomi SJ, Heilig M, Barr CS (2010) Gene-environment interactions and responses to social intrusion in male and female Rhesus monkeys. Biol Psychiat 67: Bewernick BH, et al. (2010) Nucleus accumbens deep brain stimulation decreases ratings of depression and anxiety in treatment-resistant depression. Biol Psychiat 67:

41 New from MIT Press Book blog: Children with autism - M.I.N.D. Institute, U.C. Davis

Neurobiology of Aggression and Violence: Systems, Intervention, and Impact

Neurobiology of Aggression and Violence: Systems, Intervention, and Impact Neal G. Simon, Ph. D. Professor Dept. of Biological Sciences Lehigh University Outline: Goals 1. Overview 2. Regulatory Systems