Adult rats exposed to early-life social isolation exhibit increased anxiety and conditioned fear behavior, and altered hormonal stress responses

Lukkes, Jodi L.; Mokin, Maxim; Scholl, Jamie L.; Forster, Gina L.

doi:10.1016/j.yhbeh.2008.10.014

Cited by 271 publications

(201 citation statements)

References 54 publications

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“…Consistent with the current results, postweaning social isolation, which shares features of chronic stress during adolescence, causes an increase of behaviors, or reduced extinction of behaviors, which rely on the BLA, such as learned fear responses to cues (Lukkes et al, 2009;Skelly et al, 2015;Walasek et al, 2002), but see (Morrissey et al, 2011). It also increases the responsiveness of neurons across the BLA in c-Fos studies (Toth et al, 2012), increases NMDA receptors (Gan et al, 2014), and increases the excitability of neurons in the basal nucleus (Rau et al, 2015), although the LAT has not yet been studied.…”

Section: Discussionsupporting

confidence: 91%

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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Section: Discussionsupporting

confidence: 91%

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

Zhang

Rosenkranz

2016

Neuropsychopharmacol

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“…One component of the novelty of the current findings is a demonstration of differences in the effects of stress on BA and LA neurons, and potential mechanisms for these differences. Stress exposure during development has long-lasting effects on behavior, for instance, elevated anxiety and fear behavior as well as poorer performance in spatial learning (Avital et al, 2006;Vidal et al, 2007;Lukkes et al, 2009). A recent study found that repeated restraint stress exerts different effects on the firing of BA and LA neurons in adult and adolescent rats (Zhang and Rosenkranz, 2012).…”

Section: Discussionmentioning

confidence: 99%

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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“…However, one can argue that experimental manipulations (such as earlylife stress or amphetamine withdrawal) that drive a group of animals towards greater fearand anxiety-like phenotypes also examine the underlying basis of trait fear or anxiety [e.g. 11,12]. As noted by Sylver et al [1] clinical studies most often examine trait anxiety, whereas experiments involving animal models most often focus on state anxiety and fear, and then relate these findings to concepts associated with trait anxiety.…”

Section: Goals Of the Current Reviewmentioning

confidence: 99%

“…Interestingly, CRF-induced 5-HT release in the amygdala appears to be dependent on CRF2 receptor activation in the dRN [131,133], and CRF2 receptors are known to increase 5-HT neuronal firing rates in the dRN [141]. Importantly, increased neuronal surface expression of CRF2 receptors occurs in the dRN as a result of stress [142], and increased expression of CRF2 receptors in the dRN has been observed in rat models of high anxiety [11,128,137,143]. Furthermore, CRF2 receptor antagonists infused directly into the dRN reduce heightened anxiety-like behavior in rat models of amphetamine withdrawal or early life stress [12,128].…”

Section: Monoaminergic Neurotransmission In the Amygdala: Relation Tomentioning

confidence: 99%

“…One potential promising area in the treatment of anxiety disorders may actually lie in CRF2 receptor antagonists. As outlined in Section 3.2, CRF2 receptors mediate 5-HT activity in the amygdala, are up-regulated in animal models of anxiety, and an antagonist of this receptor reduces heightened anxiety in rats [11,12,127,128,131,132,137). The challenge lies in developing non-peptide CRF2 receptor antagonists that cross the blood-brain barrier, so that the efficacy of such ligands can be determined for anxiety disorders.…”

Section: Future Potential Anxiolytic Targetsmentioning

confidence: 99%

See 1 more Smart Citation

The Role of the Amygdala in Anxiety Disorders

Forster¹,

Novick²,

Scholl³

et al. 2012

The Amygdala - A Discrete Multitasking Manager

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Adult rats exposed to early-life social isolation exhibit increased anxiety and conditioned fear behavior, and altered hormonal stress responses

Cited by 271 publications

References 54 publications

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

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

The Role of the Amygdala in Anxiety Disorders

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