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«Distribution Agreement In presenting this thesis or dissertation as a partial fulfillment of the requirements for an advanced degree from Emory ...»

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To determine whether kinetics influence the ability of synchronized IPSCs to entrain spiking and coordinate BLA neurons, we performed the following pilot study. Similar to the studies in Section 6.4.2, individual adult BLA principal neurons were patch clamped and injected with a depolarizing current step, and artificial IPSCs were injected to improve spike timing precision (Figure 7.2). In this study, we varied the slope of the decay of the artificial IPSC, to model changes in the kinetics of rhythmic IPSCs. While this data is very preliminary (n = 6), we found that the kinetics of the IPSC moderate its effects on spike timing. Specifically, IPSCs with a decay time constant (here defined as 63.2% of the duration of the off-ramp) of ~250 ms were best at improving spike timing, with a variance across 5 sweeps summed for the first 5 spikes of 291 ms2. By comparison, a faster decay of ~125 ms and a slower decay of ~630 ms yielded much larger spike timing variance of 899 and 904 ms2, respectively.

These preliminary data suggest changes to the kinetics of IPSCs will moderate the ability of PV+ interneurons to organize network oscillations. We propose that IPSCs that are too fast or too slow do not de-inactive and activate calcium currents enough, respectively, to promote oscillations. We will test these hypotheses with future studies.

With these data in mind, the effects we describe in Section 5.4.4 – that PS alters IPSC kinetics in the BLA at P14 and in adulthood – may reflect a change in the capacity of the BLA to generate network oscillations related to fear expression. It is important to keep in mind those effects were observed for single events and not the compound events that make up a rhythmic IPSC, and were not specific to afferents of PV+ interneurons, but the effect on kinetics may very well translate to rhythmic IPSCs. Future studies should therefore also address whether the reduced anxiety-like behavior we observed in PS animals reflects diminished production of network oscillations in the BLA.

7.2.3 Applying Critical Period Concepts to BLA Development One potential criticism of the arguments made herein is that assumptions are made about the applicability of the concept of critical periods to the amygdala. The concept was first described for visual cortical development, after all. The BLA is considered a “cortical-like” structure, with a similar complement of neurons and physiology to the visual cortex (Carlsen and Heimer, 1988). It is important to acknowledge this major hypothesis going forward - that critical periods of plasticity in the BLA are of consequence for emotion.

In the visual system, the term ‘critical period’ refers to a specific phenomenon: a window when sensory stimuli are capable of causing gross reorganization of the cortex. This concept lends itself nicely to considering ‘sensitive periods’ for the amygdala, when acute exposure to external stimuli like stress might cause gross reorganization of the amygdala. However, we extended the concept of critical periods to refer simply to periods of abundant plasticity, not necessarily to sensitivity to external stimuli. In this model, periods of heightened plasticity represent sensitivity to the effects not simply of acutely encountered environmental stimuli, but to cascades set in motion early in development by early life risk factors or genetically encoded alterations to basic developmental processes. Critical periods in the development of the amygdala may thereby constitute windows when risk is translated to perturbations of physiology or behavior. Critical periods could be the key to the etiology of neurodevelopmental disorders that can emerge abruptly, like autism or schizophrenia, and help explain periods of dormancy between exposure to environmental risk factors, like prenatal stress, and the manifestation of symptoms.

Several groups have broadly argued for this interpretation (Pine, 2002; Monk, 2008; King et al., 2013), but it is still theoretical.

In light of the yet theoretical nature of critical period in amygdala development, it is important to consider deficits that may be conferred by changes to the timing of developmental processes in the amygdala. Identifying specific hypotheses for the impact of changes to GABAdependent circuit maturation will be important for further characterizing our prenatal stress model. Even in the absence of a discrete “critical period” for a developmental process, akin to ocular dominance plasticity, there may be profound effects of alterations to the timing of maturation of plasticity of inputs or balancing excitation and inhibition. In general, mismatched timing of the maturation of brain regions is thought to underlie developmental changes to emotional processing. For instance, as described in Section 1.2.1, the amygdala achieving a mature state and coming “online” before the prefrontal cortex is thought to result in limited topdown suppression and hyper-activation of the amygdala during adolescence. This imbalance in developmental processes is also thought to underlie the susceptibility to psychiatric disease onset during adolescence (Drevets, 2003; Yurgelun-Todd, 2007; Casey et al., 2010; Somerville et al., 2010). Precocious maturation of the amygdala could effectively prolong the “adolescent” period of heightened emotionality.

Another proposed effect of changes to the timing of amygdala development is closely related to plasticity of inputs during visual cortical critical periods. As described in Section, we propose accelerated closing of windows of plasticity due to early amygdala activation results in altered long-range connections of the BLA. Shifting the window of plasticity early may render BLA neurons unreceptive to inputs that arrive late in development, after the window has prematurely closed. Outlined in Section, late developing inputs to the BLA include those from the frontal cortices, meaning precocious amygdala maturation may reduce the resulting connectivity of the BLA and PFC in adulthood. This model is potentially applicable to anxiety disorders, which may involve diminished top-down control and hyperactivity of the amygdala in adolescence (Correll et al., 2005; Casey et al., 2010). Importantly, ELS has been shown to diminish the integrity of the uncinate fasciculus, which connects the BLA and PFC (Eluvathingal et al., 2006; Govindan et al., 2010), suggesting stressors may influence the amygdala in the proposed manner. Conversely, delayed closure of plasticity windows may provide exaggerated sensitivity to inputs from frontal cortices, which could lead to excessive suppression of the amygdala in adulthood and the flat affect characteristic of schizophrenia. Delayed closure of critical period plasticity, a potential consequence of the diminished GABAA receptor α1 expression we reported in our novel PS model (Chapter 5), may explain the reduced anxiety-like behavior observed in PS animals.

In general, we have employed a bottom-up approach, and started by identifying effects on BLA development of a risk factor for a variety of neurodevelopmental disorders. By beginning to understand how the consequences of prenatal stress we described alter amygdala function and its integration into limbic circuitry, with attention paid to the dynamic nature of those interactions through development, the hope is to engender fresh hypotheses for specific deficits that underlie these complex disorders.

Figure 7.1 Summary of Normative Development of BLA Principal Neurons Figure 7.

1 Summary of Normative Development of BLA Principal Neurons. Schematic illustrating the representative phenotype of BLA principal neurons at 1, 2, 3, and 4 weeks of age in terms of dendritic morphology, electrophysiological responses to hyperpolarizing and depolarizing current steps, spontaneous oscillations, and synaptic transmission.

Figure 7.2 Ability of IPSCs to Organize Spiking May Be Moderated by IPSC Kinetics Figure 7.

2 Ability of IPSCs to Organize Spiking May Be Moderated by IPSC Kinetics. The effects of artificial IPSC decay kinetics on the ability to organize spiking were tested. Action potential trains were elicited in adult, BLA principal neurons from resting membrane potential using 1s depolarizing current steps. Artificial IPSCs were injected during the step to hyperpolarize the neuron, and the variance of spike times across 5 sweeps was calculated for the first 5 action potentials following the IPSC. The duration of the off-ramp of the IPSC was varied for each injected neuron, with the various stimuli injected in a random order. These preliminary results suggest the variability of spike times depend on the kinetics of the preceding IPSC. n = 6.

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