Repeated restraint stress enhances cue-elicited conditioned freezing and impairs acquisition of extinction in an age-dependent manner

Zhang, Wei; Rosenkranz, J. Amiel

doi:10.1016/j.bbr.2013.03.028

Cited by 50 publications

(40 citation statements)

References 87 publications

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“…Additional psychopathologies will also need to be addressed in future experiments. Important among these will be whether CSD leads to deficits in extinction of fear memory, as shown for other stressors (Zhang and Rosenkranz, 2013), which would be relevant to the deficient cognitive flexibility that is a common symptom of depression (Clark et al, 2009). …”

Section: Discussionmentioning

confidence: 99%

Mouse social stress induces increased fear conditioning, helplessness and fatigue to physical challenge together with markers of altered immune and dopamine function

et al. 2014

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In neuropsychiatry, animal studies demonstrating causal effects of environmental manipulations relevant to human aetiology on behaviours relevant to human psychopathologies are valuable. Such valid models can improve understanding of aetio-pathophysiology and preclinical discovery and development of new treatments. In depression, specific uncontrollable stressful life events are major aetiological factors, and subsequent generalized increases in fearfulness, helplessness and fatigue are core symptoms or features. Here we exposed adult male C57BL/6 mice to 15-day psychosocial stress with loss of social control but minimal physical wounding. One cohort was assessed in a 3-day test paradigm of motor activity, fear conditioning and 2-way avoid-escape behaviour on days 16-18, and a second cohort was assessed in a treadmill fatigue paradigm on days 19 and 29, followed by the 3-day paradigm on days 30-32. All tests used a physical aversive stimulus, namely mild, brief electroshocks. Socially stressed mice displayed decreased motor activity, increased fear acquisition, decreased 2-way avoid-escape responding (increased helplessness) and increased fatigue. They also displayed increased plasma TNF and spleen hypertrophy, and adrenal hypertrophy without hyper-corticoidism. In a third cohort, psychosocial stress effects on brain gene expression were assessed using next generation sequencing. Gene expression was altered in pathways of inflammation and G-protein coupled receptors in prefrontal cortex and amygdala; in the latter, expression of genes important in dopamine function were de-regulated including down-regulated Drd2, Adora2a and Darpp-32. This model can be applied to identify targets for treating psychopathologies such as helplessness or fatigue, and to screen compounds/biologics developed to act at these targets. AbstractIn neuropsychiatric research, animal studies that demonstrate causal effects of environmental manipulations relevant to human aetiological factors on emotional and cognitive behaviours relevant to human psychopathologies are valuable. Such valid animal models can be useful for improved understanding of aetio-pathophysiology and preclinical discovery and development of new treatments. In depression, specific uncontrollable stressful life events are major aetiological factors, and subsequent generalized increases in fearfulness, helplessness and fatigue are core psychopathology symptoms or features. In the present study we exposed adult male C57BL/6 mice to an environmental manipulation of 15-day psychosocial stress with loss of social control but with minimal physical wounding. One cohort of stressed and control mice was assessed in a novel 3-day test paradigm of motor activity, fear conditioning and 2-way avoid-escape behaviour on days 16-18, and a second cohort was assessed in a treadmill fatigue paradigm on days 19 and 29, followed by the 3-day paradigm on days 30-32. All tests used a physical aversive stimulus, namely mild, brief electroshocks. The socially stressed mice displayed dec...

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Section: Discussionmentioning

confidence: 99%

Mouse social stress induces increased fear conditioning, helplessness and fatigue to physical challenge together with markers of altered immune and dopamine function

et al. 2014

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“…Studies have repeatedly demonstrated that the increased activity of the amygdala in adult male rats after stress parallels increased anxiety (Vyas et al, 2004;DoremusFitzwater et al, 2009;Rosenkranz et al, 2010) and production of behaviors that rely on the BLA, such as such as freezing in response to a fear-conditioned cue (Conrad et al, 1999;Rau et al, 2005;Rodriguez Manzanares et al, 2005;ToledoRodriguez and Sandi, 2007;Atchley et al, 2012;Zhang and Rosenkranz, 2013). Relatively less is known about the effects of stress on amygdala-dependent behaviors in adolescents; however, in several studies increased fear conditioning is accompanied by an impairment of fear extinction in adolescents and enhanced generalization of fear (Morrissey et al, 2011;Zhang and Rosenkranz, 2013;Muller et al, 2014;Padival et al, 2015). Both of these processes are sensitive to GABA within the BLA (Davis and Myers, 2002;Shaban et al, 2006;Lin et al, 2009;Sangha et al, 2009;Makkar et al, 2010;Lange et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Effects of Repeated Stress on Age-Dependent GABAergic Regulation of the Lateral Nucleus of the Amygdala

Zhang

Rosenkranz

2016

Neuropsychopharmacol

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The adolescent age is associated with lability of mood and emotion. The onset of depression and anxiety disorders peaks during adolescence and there are differences in symptomology during adolescence. This points to differences in the adolescent neural circuitry that underlies mood and emotion, such as the amygdala. The human adolescent amygdala is more responsive to evocative stimuli, hinting to less local inhibitory regulation of the amygdala, but this has not been explored in adolescents. The amygdala, including the lateral nucleus (LAT) of the basolateral amygdala complex, is sensitive to stress. The amygdala undergoes maturational processes during adolescence, and therefore may be more vulnerable to harmful effects of stress during this time period. However, little is known about the effects of stress on the LAT during adolescence. GABAergic inhibition is a key regulator of LAT activity. Therefore, the purpose of this study was to test whether there are differences in the local GABAergic regulation of the rat adolescent LAT, and differences in its sensitivity to repeated stress. We found that LAT projection neurons are subjected to weaker GABAergic inhibition during adolescence. Repeated stress reduced in vivo endogenous and exogenous GABAergic inhibition of LAT projection neurons in adolescent rats. Furthermore, repeated stress decreased measures of presynaptic GABA function and interneuron activity in adolescent rats. In contrast, repeated stress enhanced glutamatergic drive of LAT projection neurons in adult rats. These results demonstrate age differences in GABAergic regulation of the LAT, and age differences in the mechanism for the effects of repeated stress on LAT neuron activity. These findings provide a substrate for increased mood lability in adolescents, and provide a substrate by which adolescent repeated stress can induce distinct behavioral outcomes and psychiatric symptoms.

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“…Stress-group rats were placed in a restraint hemicylinder for 20 min per session, one session per day on 7 out of 9 consecutive days. Previous behavioral and electrophysiological studies demonstrate that this is an effective protocol to induce changes in BLA-dependent behaviors and BLA neuronal firing (Rosenkranz et al, 2010;Atchley et al, 2012;Zhang and Rosenkranz, 2012;Zhang and Rosenkranz, 2013). Three different sizes of restraint hemicylinders were used to fit the size of the rats such that movement of the body was restricted.…”

Section: Repeated Restraint Stressmentioning

confidence: 99%

“…Immature rodents display greater hormonal changes after stress than adults (Meaney et al, 1985;Sapolsky and Meaney, 1986;Walker et al, 1991;Romeo et al, 2006) and greater behavioral changes (Einon and Morgan, 1977;Stone and Quartermain, 1997;Hascoet et al, 1999;Spear, 2000;Luine et al, 2007;Toledo-Rodriguez and Sandi, 2007;Zhang and Rosenkranz, 2013). There are several brain regions that contribute to the effects of stress on affective behaviors.…”

Section: Introductionmentioning

confidence: 99%

“…The BLA is sensitive to hormones (eg, glucocorticoids and corticotrophin-releasing hormone) that become elevated in response to stress (Rainnie et al, 1992;Duvarci and Pare, 2007;Sandi et al, 2008;Giesbrecht et al, 2010). Furthermore, repeated stress in rats leads to long-lasting changes in BLA-dependent behavior (Conrad et al, 1999;Toledo-Rodriguez and Sandi, 2007;Zhang and Rosenkranz, 2013) and BLA neuronal structure of adult rats (Vyas et al, 2002;Padival et al, 2013b). Repeated stress also causes hyperactivity of BLA pyramidal neurons in adult rats in vivo (Rosenkranz et al, 2010;Zhang and Rosenkranz, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Distinct Effects of Repeated Restraint Stress on Basolateral Amygdala Neuronal Membrane Properties in Resilient Adolescent and Adult Rats

Hetzel

Rosenkranz

2014

Neuropsychopharmacol

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Severe and repeated stress has damaging effects on health, including initiation of depression and anxiety. Stress that occurs during development has long-lasting and particularly damaging effects on emotion. The basolateral amygdala (BLA) plays a key role in many affective behaviors, and repeated stress causes different forms of BLA hyperactivity in adolescent and adult rats. However, the mechanism is not known. Furthermore, not every individual is susceptible to the negative consequences of stress. Differences in the effects of stress on the BLA might contribute to determine whether an individual will be vulnerable or resilient to the effects of stress on emotion. The purpose of this study is to test the cellular underpinnings for age dependency of BLA hyperactivity after stress, and whether protective changes occur in resilient individuals. To test this, the effects of repeated stress on membrane excitability and other membrane properties of BLA principal neurons were compared between adult and adolescent rats, and between vulnerable and resilient rats, using in vitro whole-cell recordings. Vulnerability was defined by adrenal gland weight, and verified by body weight gain after repeated restraint stress, and fecal pellet production during repeated restraint sessions. We found that repeated stress increased the excitability of BLA neurons, but in a manner that depended on age and BLA subnucleus. Furthermore, stress resilience was associated with an opposite pattern of change, with increased slow afterhyperpolarization (AHP) potential, whereas vulnerability was associated with decreased medium AHP. The opposite outcomes in these two populations were further distinguished by differences of anxiety-like behavior in the elevated plus maze that were correlated with BLA neuronal excitability and AHP. These results demonstrate a substrate for BLA hyperactivity after repeated stress, with distinct membrane properties to target, as well as age-dependent factors that contribute to resilience to the effects of stress.

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Repeated restraint stress enhances cue-elicited conditioned freezing and impairs acquisition of extinction in an age-dependent manner

Cited by 50 publications

References 87 publications

Mouse social stress induces increased fear conditioning, helplessness and fatigue to physical challenge together with markers of altered immune and dopamine function

Mouse social stress induces increased fear conditioning, helplessness and fatigue to physical challenge together with markers of altered immune and dopamine function

Effects of Repeated Stress on Age-Dependent GABAergic Regulation of the Lateral Nucleus of the Amygdala

Distinct Effects of Repeated Restraint Stress on Basolateral Amygdala Neuronal Membrane Properties in Resilient Adolescent and Adult Rats

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