Chronic stress causes amygdala hyperexcitability in rodents.

Department of Cellular and Molecular Pharmacology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.
Biological psychiatry (Impact Factor: 8.93). 04/2010; 67(12):1128-36. DOI: 10.1016/j.biopsych.2010.02.008
Source: PubMed

ABSTRACT Chronic stress is a major health concern, often leading to depression, anxiety, or when severe enough, posttraumatic stress disorder. While many studies demonstrate that the amygdala is hyperresponsive in patients with these disorders, the cellular neurophysiological effects of chronic stress on the systems that underlie psychiatric disorders, such as the amygdala, are relatively unknown.
In this study, we examined the effects of chronic stress on the activity and excitability of amygdala neurons in vivo in rats. We used in vivo intracellular recordings from single neurons of the lateral amygdala (LAT) to measure neuronal properties and determine the cellular mechanism for the effects of chronic stress on LAT neurons.
We found a mechanism for the effects of chronic stress on amygdala activity, specifically that chronic stress increased excitability of LAT pyramidal neurons recorded in vivo. This hyperexcitability was caused by a reduction of a regulatory influence during action potential firing, facilitating LAT neuronal activity. The effects of stress on excitability were occluded by agents that block calcium-activated potassium channels and reversed by pharmacological enhancement of calcium-activated potassium channels.
These data demonstrate a specific channelopathy that occurs in the amygdala after chronic stress. This enhanced excitability of amygdala neurons after chronic stress may explain the observed hyperresponsiveness of the amygdala in patients with posttraumatic stress disorder and may facilitate the emergence of depression or anxiety in other patients.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Learning-induced modulation of neuronal intrinsic excitability is a metaplasticity mechanism that can impact the acquisition of new memories. Although the amygdala is important for emotional learning and other behaviors, including fear and anxiety, whether learning alters intrinsic excitability within the amygdala has received very little attention. Fear conditioning was combined with intracellular recordings to investigate the effects of learning on the intrinsic excitability of lateral amygdala (LA) neurons. To assess time-dependent changes, brain slices were prepared either immediately or 24-h post-conditioning. Fear conditioning significantly enhanced excitability of LA neurons, as evidenced by both decreased afterhyperpolarization (AHP) and increased neuronal firing. These changes were time-dependent such that reduced AHPs were evident at both time points whereas increased neuronal firing was only observed at the later (24-h) time point. Moreover, these changes occurred within a subset (32%) of LA neurons. Previous work also demonstrated that learning-related changes in synaptic plasticity are also evident in less than one-third of amygdala neurons, suggesting that the neurons undergoing intrinsic plasticity may be critical for fear memory. These data may be clinically relevant as enhanced LA excitability following fear learning could influence future amygdala-dependent behaviors.
    Learning & memory (Cold Spring Harbor, N.Y.) 02/2014; 21(3):161-170. · 4.08 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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 potential (AHP) while 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.Neuropsychopharmacology accepted article preview online, 12 March 2014; doi:10.1038/npp.2014.60.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 03/2014; · 8.68 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Studies of stress effects on the brain have traditionally focused on neurons, without considering the cerebral microcirculation. Here we report that stress impairs neurovascular coupling (NVC), the process that matches neuronal activity with increased local blood flow. A stressed phenotype was induced in male rats by administering a 7-d heterotypical stress paradigm. NVC was modeled by measuring parenchymal arteriole (PA) vasodilation in response to neuronal stimulation in amygdala brain slices. After stress, vasodilation of PAs to neuronal stimulation was greatly reduced, and dilation of isolated PAs to external K(+) was diminished, suggesting a defect in smooth muscle inwardly rectifying K(+) (KIR) channel function. Consistent with these observations, stress caused a reduction in PA KIR2.1 mRNA and smooth muscle KIR current density, and blocking KIR channels significantly inhibited NVC in control, but not in stressed, slices. Delivery of corticosterone for 7 d (without stressors) or RU486 (before stressors) mimicked and abrogated NVC impairment by stress, respectively. We conclude that stress causes a glucocorticoid-mediated decrease in functional KIR channels in amygdala PA myocytes. This renders arterioles less responsive to K(+) released from astrocytic endfeet during NVC, leading to impairment of this process. Because the fidelity of NVC is essential for neuronal health, the impairment characterized here may contribute to the pathophysiology of brain disorders with a stress component.
    Proceedings of the National Academy of Sciences 05/2014; · 9.81 Impact Factor

Full-text (2 Sources)

Available from
May 26, 2014