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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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Some effects of neurotransmission on the maturation and survival of interneurons are mediated by brain-derived neurotrophic factor (BDNF), which is secreted in response to neuronal activity (Rutherford et al., 1997; de Lima et al., 2004). BDNF secretion can be caused by activation of GABA receptors (Fiorentino et al., 2009). BDNF accelerates the emergence of developmental CPs, parvalbumin expression, and perisomatic baskets (Huang et al., 1999; Patz et al., 2004; Fiorentino et al., 2009). It also accelerates the maturation of cultured PV+ interneurons, increasing their somatic diameter, dendritic branching, action potential frequency, and synaptic strength (Berghuis et al., 2004). In addition, another target-derived signaling molecule that interacts with BDNF, bone morphogenetic protein 4 (BMP4), promotes parvalbumin emergence and increases the density of PV+ interneurons in the mature cortex (Mukhopadhyay et al., 2009;

Takatoh and Wang, 2012).

Thus, changes in neuronal activity or GABAergic transmission in the developing BLA following ELS could influence BDNF secretion and alter the maturation of PV+ interneurons and the timing of CPs. In fact, the developing amygdala may be more likely to experience stressinduced changes in its activity; for instance, chronic stress in adolescents increases the spontaneous activity of neurons in the BLA and impairs fear extinction, but the same stressor in adulthood recapitulates neither effect (Zhang and Rosenkranz, 2012, 2013). This study comprises our entire, limited knowledge regarding the development of amygdala neuron activity. No study has yet to describe the developmental trajectory of BLA neuron electrophysiology, let alone when the effects of ELS may first perturb this process. We address this knowledge gap in Chapter 2, providing a foundation to interpret the effects of ELS on amygdala inhibition and, therefore, CPs in emotional development.

1.4.1.3 ELS Alters Development of the BLA GABA System Similar to research on the effects of ELS on the activity of developing amygdala neurons, studies on the effects on development of GABA systems in the BLA are lacking. One study found PS reduces the expression of the GABAA receptor γ2 subunit at P14 and P22, but no consistent effect on the α1 subunit was detected (Laloux et al., 2012). Several more have described changes in adulthood, but the time course and therefore the effects on developmental CPs are unknown.

For instance, ELS increases the number of PV+ interneurons in the adult BLA nearly 4-fold (however, see Giachino et al., 2007; Seidel et al., 2008). Stress from P27-30 reduced the expression in the adult amygdala of the GABAA receptor α1 subunit relative to α3, promoting an immature phenotype (Jacobson-Pick et al., 2008). A similar reduction of α1 expression in the adult BLA is caused by poor maternal care (Caldji et al., 2003). In addition, reduced α1 expression due to ELS has been observed in the adult hippocampus (Hsu et al., 2003). These findings seem contradictory, since PV+ neurons preferentially innervate α1-containing synapses, but the two measures are influenced oppositely by ELS. Further studies are needed to characterize the trajectory of ELS effects on amygdala inhibition, particularly PV+ interneuron, PNN, and GABAA receptor α1 subunit emergence, to identify the potential impact on developmental CPs.

We address this knowledge gap in Chapter 5.

1.4.2 Experiential Factors Promoting Resiliency A large number of studies have attempted to elucidate the mechanisms by which ELS leads to vulnerability for psychiatric illness. However, the identification of early life factors that promote resiliency will be equally important for devising interventional treatment. Conceptual models of fetal programming suggest early exposure to stress can program subsequent stress responses to adapt the offspring and improve reproductive fitness for highly stressful environments (for review, see Glover, 2011). While many reports discussed in Section 1.1.2.1 find negative outcomes following PS, contrasting reports support a role for some types of PS in promoting resiliency by buffering against later life stress (Lyons et al., 2009; Green et al., 2011).

There may in fact be a nonlinear relationship between ELS and anxiety outcomes, such that moderate PS exposure is protective for offspring (Edge et al., 2009). Genetic factors likely moderate the impact of ELS, contributing to individual variation in risk and resiliency (for review, see Gillespie et al., 2009).

Resiliency can also be promoted by exposure to certain types of parenting early in life.

Variations in maternal care are meaningful for the development of emotional behavior and stress responses in the offspring. Diorio and Meaney argue for the adaptive nature of this sensitivity to maternal behavior, such that care can reflect the inherent risk in the environment and promote behavioral responses with immediate adaptive value, sometimes at the cost for emotional dysfunction later in life (2007). Specific types of maternal care are known to affect the development of the HPA axis in offspring (for review, see Francis et al., 1999a). For instance, early maternal nurturing in rhesus monkeys buffers HPA axis responses (Sanchez, 2006) and reduces the expression of glucocorticoids and CRF (Korosi and Baram, 2009). Importantly, stress reactivity can also be reduced by other forms of early experience, as environmental enrichment at the time of weaning is anxiolytic and reduces CRF receptor expression in the BLA (Sztainberg et al., 2010).





Maternal care seems to promote resiliency by moderating the effects of ELS on the amygdala. For example, while rats normally exhibit conditioned avoidance starting at P10 (switched from attraction learning, see Section 1.3.3.3) the presence of a rat’s mother or the mother’s odor is sufficient at P15 to reproduce the immature, attraction learning. Maternal presence acts by suppressing shock-induced glucocorticoid release, which prevents amygdala activation and, therefore, fear conditioning (Moriceau and Sullivan, 2006). Maternal care can therefore serve to dampen amygdala activation, which may prevent the stress-induced, precocious maturation of the amygdala described in Section 1.4.1.1.

Maternal care can also influence outcomes of the amygdala GABA system. Types of naturally occurring maternal care that reduce fearfulness and HPA axis activation in adulthood also increase expression in the BLA of GABAA receptor α1, α5, and γ2 subunits (Caldji et al., 2003). Interestingly, increased γ2 subunit expression in the BLA and a corresponding reduction of anxiety-like behavior can also be elicited by simply handling animals in infancy (Caldji et al., 2000). These findings strikingly contrast those on the effects of ELS, which reduces γ2 and α1 subunit expression in the BLA (Caldji et al., 2003; Jacobson-Pick et al., 2008; Laloux et al., 2012). Early life factors promoting resiliency may do so by opposing the effects of ELS on GABAergic transmission in the developing amygdala.

1.5 Conceptual Summary This chapter has established several important points moving forward: 1) it is important to consider trajectories of development to understand the etiology of neurodevelopmental disorders, 2) dysfunction of the BLA is implicated in the pathophysiology of several neurodevelopmental disorders, including anxiety disorders, 3) the changes that occur in the developing amygdala likely contribute to early life emergence of anxiety disorders and vulnerability to risk factors, 4) understanding how risk factors like ELS influence amygdala development will require filling large knowledge gaps concerning the normative development of amygdala neurons and physiology, and 5) GABAergic transmission is a prime candidate to mediate the effects of ELS because it regulates both the maturation of neural circuits and adult BLA function.

The remainder of this thesis describes individual studies that address knowledge gaps concerning BLA function and development, focusing on the GABA system and the effects of PS.

Chapters 2 & 3 address the normative maturation of BLA principal neuron electrophysiology and morphology, respectively. Chapter 4 describes the maturation of GABAergic transmission in the BLA. Using those studies as a foundation, the effects of PS on the trajectory of BLA development is covered in Chapter 5, again with special attention paid to GABAergic transmission and PV+ interneurons. Considering the changes to BLA neurons and GABAergic transmission following PS, the function of PV+ interneurons in the BLA is explored Chapter 6.

Finally, Chapter 7 includes a summary of findings, with focus on integrating the effects of PS with the normative changes to BLA physiology and function.

Figure 1.1: Schematic of connections of the basolateral amygdala.

Figure 1.1: Schematic of connections of the basolateral amygdala.

The basolateral amygdala (BLA) has reciprocal connections with upstream brain regions including primary sensory cortices, prefrontal cortices (PFC) which provide top-down control (including medial, ventromedial, and ventrolateral PFC as well as anterior cingulate cortex), and the lateral amygdala (LA). The BLA sends afferents for regulating emotional behavior to the central amygdala (CeA) and bed nucleus of the stria terminalis (BNST), which promote behavioral responses to aversive stimuli (connections depicted in red), and to the nucleus accumbens (NAcc), which promote behavioral responses to appetitive stimuli (connections depicted in green).

Chapter 2: Postnatal development of electrophysiological properties of principal neurons in the rat basolateral amygdala1 Adapted from: Ehrlich DE*, Ryan SJ*, Rainnie DG (2012). Postnatal development of electrophysiological properties of principal neurons in the rat basolateral amygdala. J Physiol 590 (19); 4819-38.

2.1 Abstract The basolateral amygdala (BLA) is critically involved in the pathophysiology of psychiatric disorders, which often emerge during brain development. Several studies have characterized postnatal changes to the morphology and biochemistry of BLA neurons, and many more have identified sensitive periods of emotional maturation. However, it is impossible to determine how BLA development contributes to emotional development or the etiology of psychiatric disorders because no study has characterized the physiological maturation of BLA neurons. We addressed this critical knowledge gap using whole-cell patch clamp recording in rat BLA principal neurons to measure electrophysiological properties at postnatal day 7 (P7), P10, P14, P21, P28, and after P35. We show that intrinsic properties of these neurons undergo significant transitions before P21 and reach maturity around P28. Specifically, we observed significant reductions in input resistance and membrane time-constant of nearly ten- and fourfold, respectively, from P7 to P28. The frequency selectivity of these neurons to input also changed significantly, with peak resonance frequency increasing from 1.0 Hz at P7 to 5.7 Hz at P28. In the same period, maximal firing frequency significantly increased and doublets and triplets of action potentials emerged. Concomitantly, individual action potentials became significantly faster, firing threshold hyperpolarized 6.7 mV, the medium AHP became faster and shallower, and a fast AHP emerged. These results demonstrate neurons of the BLA undergo vast change throughout postnatal development, and studies of emotional development and treatments for juvenile psychiatric disorders should consider the dynamic physiology of the immature BLA.

2.2 Introduction The mechanisms by which early-life experiences impact the developing amygdala remain largely unknown because our understanding of amygdala physiology is based almost exclusively on research conducted in adult animals. Consequently, to better understand how early-life events can impact affective behavior later in life, a critical first step is to chart the normative developmental trajectory of the amygdala. Here we provide the first evidence for electrophysiological changes in the developing amygdala.

The few studies that have addressed other aspects of amygdala development reveal a highly dynamic neuronal environment in juvenile rodents, which does not begin to stabilize until at least postnatal day 28 (P28) (Morys et al., 1998; Berdel and Morys, 2000; Brummelte et al., 2007; Davila et al., 2008). As mentioned in Chapter 1, the neuronal composition of the BLA is highly dynamic during the first postnatal month. Numerous in the BLA from birth, principal neurons account for about 85% of all neurons in the adult BLA (McDonald, 1985; McDonald and Pearson, 1989; Berdel et al., 1997a). In contrast, interneurons expressing parvalbumin and/or calbindin, which comprise the majority of interneurons, first appear in the BLA around P14 and do not reach mature levels until about P25-30 (Berdel and Morys, 2000). In parallel with these changes, the number of synaptic contacts in the BLA nearly triples, while cell soma size doubles, and neuronal density halves between P7 and P14 (Berdel et al., 1997a; Morys et al., 1998). These changes are, in turn, mirrored by changes in thalamic and cortical inputs, which only emerge at P7 and are continually refined until P26 (Bouwmeester et al., 2002b). Finally, the protein expression of key ion channels in BLA neurons changes on a similar time scale (Vacher et al., 2006).

We and others have shown that the normal function of the adult BLA is tightly regulated by a reciprocal interaction between principal neurons and GABAergic interneurons (See Chapter 1.2.3; Rainnie (See Chapter 1.2.3; Rainnie et al., 1991b, a; Ehrlich et al., 2009; Ryan et al., 2012).

Given the studies outlined above, the neural circuitry of the BLA, and hence its function, would be predicted to change dramatically across development. As outlined in Chapter 1.3.3.1, at P7, rats approach an aversively-conditioned stimulus, only expressing the mature avoidance behavior after P10 (Sullivan et al., 2000). Similarly, adult-like expression of fear-potentiated startle does not emerge until P23 (Hunt et al., 1994; Richardson et al., 2000). Other aspects of conditioned fear, including the emergence of trace conditioning and reinstatement, change on a similar timescale (Campbell and Ampuero, 1985; Moye and Rudy, 1987; Kim and Richardson, 2007).



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