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: 10.26). 04/2010; 67(12):1128-36. DOI: 10.1016/j.biopsych.2010.02.008
Source: PubMed


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.

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Available from: Jeremy Amiel Rosenkranz
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    • "The basolateral amygdala complex (BLA) is considered to be a crucial neural hub for the modulation of anxietyrelated and emotionally-driven behaviors (Davis, 1992; Bremner, 2004; Tye et al., 2011; Dias et al., 2013; Felix-Ortiz et al., 2013; Janak and Tye, 2015; Namburi et al., 2015; Allsop et al., 2014). In humans, the BLA exhibits hyperactivity in most forms of anxiety disorders (Rauch et al., 2003), and in rodents BLA hyperexcitability and hypertrophy is associated with an enduring facilitation of anxiety-like behaviors (Roozendaal et al., 2009; Rosenkranz et al., 2010). Along with a critical role in anxiety , research has established a crucial role for the BLA in the modulation of social behavior (Kling and Steklis, 1976; Katayama et al., 2009; Bickart et al., 2014; Felix-Ortiz and Tye, 2014). "
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    ABSTRACT: The basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) modulate anxiety and social behaviors. It remains to be elucidated, however, whether direct projections from the BLA to the mPFC play a functional role in these behaviors. We used optogenetic approaches in behaving mice to either activate or inhibit BLA inputs to the mPFC during behavioral assays that assess anxiety-like behavior and social interaction. Channelrhodopsin-2 (ChR2)-mediated activation of BLA inputs to the mPFC produced anxiogenic effects in the elevated-plus maze and open-field test, whereas halorhodopsin (NpHR)-mediated inhibition produced anxiolytic effects. Furthermore, activation of the BLA-mPFC pathway reduced social interaction in the resident-intruder test, whereas inhibition facilitated social interaction. These results establish a causal relationship between activity in the BLA-mPFC pathway and the bidirectional modulation of anxiety and social behaviors. Copyright © 2015. Published by Elsevier Ltd.
    Preview · Article · Jul 2015 · Neuroscience
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    • "Likewise, positive modulation of SK channels, and the subsequent enhancement of AHPs, reduces action potential frequency (Lujan et al., 2009; Hopf et al., 2010b). Importantly, disruption of SK channel activity and the ensuing dysregulation of neuronal output appear to play an important role in the neurobiological response to stressors such as fear conditioning (Santini et al., 2008; McKay et al., 2009; Motanis et al., 2014), restraint stress (Rosenkranz et al., 2010; Hetzel and Rosenkranz, 2014), and chronic exposure to ethanol (Hopf et al., 2010a, 2010b; Mulholland et al., 2011). Over the years, the neuromodulator adenosine and its receptor system have gained appreciation as key regulators of neuronal excitability (Dunwiddie and Masino, 2001). "
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    ABSTRACT: The basolateral amygdala (BLA) plays a critical role in the etiology of anxiety disorders and addiction. Pyramidal neurons, the primary output cells of this region, display increased firing following exposure to stressors and it is thought that this increase in excitability contributes to stress responsivity and the expression of anxiety-like behaviors. However, much remains unknown about the underlying mechanisms that regulate the intrinsic excitability of BLA pyramidal neurons. Ex vivo gramicidin perforated patch recordings were conducted in current clamp mode where hyper- and depolarizing current steps were applied to BLA pyramidal neurons to assess the effects of adenosine A2A receptor modulation on intrinsic excitability. Activation of adenosine A2A receptors with the selective A2A receptor agonist CGS-21680 significantly increased the firing rate of BLA pyramidal neurons in rat amygdala brain slices, likely via inhibition of the slow afterhyperpolarization potential. Both of these A2A receptor-mediated effects were blocked by pre-application of a selective A2A receptor antagonist (ZM-241685) or by intra-pipette infusion of a PKA inhibitor, suggesting a postsynaptic locus of A2A receptors on BLA pyramidal neurons. Interestingly, bath application of the A2A receptor antagonist alone significantly attenuated BLA pyramidal cell firing, consistent with a role for tonic adenosine in the regulation of the intrinsic excitability of these neurons. Collectively, these data suggest that adenosine, via activation of A2A receptors, may directly facilitate BLA pyramidal cell output, providing a possible balance for the recently described inhibitory effects of adenosine A1 receptor activation on glutamatergic excitation of BLA pyramidal cells. © The Author 2014. Published by Oxford University Press on behalf of CINP.
    Full-text · Article · Feb 2015 · The International Journal of Neuropsychopharmacology
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    • "It was observed that GAD 65 expression in the medial amygdala (MeA) of males negatively correlated with spatial learning: increased errors were associated with less GAD 65 expression in the MeA. This brain region is intriguing because it is responsible for emotional regulation [63] and is impacted by stress [17] [65] [69] [78] [79]. It is fascinating that the distribution of the data shows the Str-Imm males clustered together and with low GAD 65 expression. "
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    ABSTRACT: Chronic restraint stress alters hippocampal-dependent spatial learning and memory in a sex-dependent manner, impairing spatial performance in male rats and leaving intact or facilitating performance in female rats. Moreover, these stress-induced spatial memory deficits improve following post-stress recovery in males. The current study examined whether restraint administered in an unpredictable manner would eliminate these sex differences and impact a post-stress period on spatial ability and limbic glutamic acid decarboxylase (GAD65) expression. Male (n=30) and female (n=30) adult Sprague-Dawley rats were assigned to non-stressed control (Con), chronic stress (Str-Imm), or chronic stress given a post-stress recovery period (Str-Rec). Stressed rats were unpredictably restrained for 21 days using daily non-repeated combinations of physical context, duration, and time of day. Then, all rats were tested on the radial arm water maze (RAWM) for two days and given one retention trial on the third day, with brains removed 30minutes later to assess GAD65 mRNA. In Str-Imm males, deficits occurred on day 1 of RAWM acquisition, an impairment that was not evident in the Str-Rec group. In contrast, females did not show significant outcomes following chronic stress or post-stress recovery. In males, amygdalar GAD65 expression negatively correlated with RAWM performance on day 1. In females, hippocampal CA1 GAD65 positively correlated with RAWM performance on day 1. These results demonstrate that GABAergic function may contribute to the sex differences observed following chronic stress. Furthermore, unpredictable restraint and a recovery period failed to eliminate the sex differences on spatial learning and memory. Copyright © 2015. Published by Elsevier B.V.
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