Post-traumatic stress disorder (PTSD) is a debilitating condition that develops in a proportion of individuals following a traumatic event. Despite recent advances, ethical limitations associated with human research impede progress in understanding PTSD. Fortunately, much effort has focused on developing animal models to help study the pathophysiology of PTSD. Here, we provide an overview of animal PTSD models where a variety of stressors (physical, psychosocial, or psychogenic) are used to examine the long-term effects of severe trauma. We emphasize models involving predator threat because they reproduce human individual differences in susceptibility to, and in the long-term consequences of, psychological trauma.
Humans with post-traumatic stress disorder (PTSD) are deficient at extinguishing conditioned fear responses. A study of identical twins concluded that this extinction deficit does not predate trauma but develops as a result of trauma. The present study tested whether the Lewis rat model of PTSD reproduces these features of the human syndrome. Lewis rats were subjected to classical auditory fear conditioning before or after exposure to a predatory threat that mimics a type of traumatic stress that leads to PTSD in humans. Exploratory behavior on the elevated plus maze 1 wk after predatory threat exposure was used to distinguish resilient vs. PTSD-like rats. Properties of extinction varied depending on whether fear conditioning and extinction occurred before or after predatory threat. When fear conditioning was carried out after predatory threat, PTSD-like rats showed a marked extinction deficit compared with resilient rats. In contrast, no differences were seen between resilient and PTSD-like rats when fear conditioning and extinction occurred prior to predatory threat. These findings in Lewis rats closely match the results seen in humans with PTSD, thereby suggesting that studies comparing neuronal interactions in resilient vs. at-risk Lewis rats might shed light on the causes and pathophysiology of human PTSD.
Recent findings implicate the central lateral amygdala (CeL) in conditioned fear. Indeed, CeL contains neurons exhibiting positive (CeL-On) or negative (CeL-Off) responses to fear-inducing conditioned stimuli (CSs). In mice, these cells differ in their expression of protein kinase Cδ (PKCδ) and physiological properties. CeL-Off cells are PKCδ(+) and late firing (LF), whereas CeL-On cells are PKCδ(-) and express a regular-spiking (RS) or low-threshold bursting (LTB) phenotype. However, the scarcity of LF cells in rats raises questions about the correspondence between the organization of CeL in mice and rats. Therefore, we studied the PKCδ expression, morphological properties, synaptic responsiveness, and fear conditioning-induced plasticity of rat CeL neurons. No PKCδ(+) LF cells were encountered, but ≈20-25% of RS and LTB neurons were PKCδ(+). Compared with RS neurons, a higher proportion of LTB cells projected to central medial amygdala (CeM) and they had fewer primary dendritic branches, yet the amplitude of excitatory postsynaptic potentials (EPSPs) evoked by lateral amygdala (LA) stimulation was similar in RS and LTB cells. In contrast, LA-evoked inhibitory postsynaptic potentials (IPSPs) had a higher amplitude in LTB than RS neurons. Finally, fear conditioning did not induce plasticity at LA inputs to RS or LTB neurons. These findings point to major species differences in the organization of CeL. Since rat LTB cells are subjected to stronger feedforward inhibition, they are more likely to exhibit inhibitory CS responses than RS cells. This is expected to cause a disinhibition of CeM fear output neurons and therefore an increase in fear expression.
In the mammalian hippocampus, adult-born granule cells (abGCs) contribute to the function of the dentate gyrus (DG). Disruption of the DG circuitry causes spontaneous recurrent seizures (SRS), which can lead to epilepsy. Although abGCs contribute to local inhibitory feedback circuitry, whether they are involved in epileptogenesis remains elusive. Here, we identify a critical window of activity associated with the aberrant maturation of abGCs characterized by abnormal dendrite morphology, ectopic migration, and SRS. Importantly, in a mouse model of temporal lobe epilepsy, silencing aberrant abGCs during this critical period reduces abnormal dendrite morphology, cell migration, and SRS. Using mono-synaptic tracers, we show silencing aberrant abGCs decreases recurrent CA3 back-projections and restores proper cortical connections to the hippocampus. Furthermore, we show that GABA-mediated amplification of intracellular calcium regulates the early critical period of activity. Our results demonstrate that aberrant neurogenesis rewires hippocampal circuitry aggravating epilepsy in mice.
Electroencephalogram (EEG) recordings in Fragile X syndrome (FXS) patients have revealed enhanced sensory responses, enhanced resting "gamma frequency" (30-100 Hz) activity, and a decreased ability for sensory stimuli to modulate cortical activity at gamma frequencies. Similar changes are observed in the FXS model mouse-the Fmr1 knockout. These alterations may become effective biomarkers for diagnosis and treatment of FXS. Therefore, it is critical to better understand what circuit properties underlie these changes. We employed Channelrhodopsin2 to optically activate local circuits in the auditory cortical region in brain slices to examine how changes in local circuit function may be related to EEG changes. We focused on layers 2/3 and 5 (L2/3 and L5). In Fmr1 knockout mice, light-driven excitation of L2/3 revealed hyperexcitability and increased gamma frequency power in both local L2/3 and L5 circuits. Moreover, there is increased synchrony in the gamma frequency band between L2/3 and L5. Hyperexcitability and increased gamma power were not observed in L5 with L5 light-driven excitation, indicating that these changes were layer-specific. A component of L2/3 network hyperexcitability is independent of ionotropic receptor mediated synaptic transmission and may be mediated by increased intrinsic excitability of L2/3 neurons. Finally, lovastatin, a candidate therapeutic compound for FXS that targets ERK signaling did not normalize changes in gamma activity. In conclusion, hyperactivity and increased gamma activity in local neocortical circuits, together with increased gamma synchrony between circuits, provide a putative substrate for EEG alterations observed in both FXS patients and the FXS mouse model.
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