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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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6: BLA principal neurons exhibited a modifiable intrinsic resonance and a membrane potential oscillation that was facilitated by compound IPSPs. (A1-D1) Principal neuron membrane potential response to injection of a sinusoidal current with constant amplitude and linearly changing frequency (0-12 Hz) in the presence of various drug cocktails. All neurons were held at baseline of -60 mV. (A1) Typical voltage response to the sinusoidal current in TTX (1 µM). The resonance of BLA principal neurons can be enhanced by application of 4-AP (B1, 500 µM) and the adenylyl cyclase activator, forskolin (C1, 10 µM), and is abolished by application of NiCl (500 µM, D1). Analysis of power spectra (E) shows that the enhancement of resonance by 4-AP and forskolin is significantly different from baseline (p 0.05). (A2-D3) Intrinsic membrane oscillations of BLA principal neurons, held at -60 mV, in response to a steady depolarizing current injection (A2-D2) and in response to the same current injection with superimposed IPSPs (A3-D3). Similar to resonant properties, membrane oscillations are enhanced by application of 4-AP and forskolin, and abolished in NiCl. Injection of artificial IPSPs in A3-D3 significantly enhanced the amplitude and duration of oscillations (F and G;

spectrograms illustrate data from C2 and C3 respectively).

Figure 6.7: The peak power of the membrane potential oscillation was sensitive to modulation of IA and IT and activation of PKA Figure 6.

7: The peak power of the membrane potential oscillation was sensitive to modulation of IA and IT and activation of PKA. Power spectra of MPOs in BLA PNs in response to a depolarizing step with artificial IPSPs, with mean (solid lines) and 95% confidence intervals (shaded region). Frequencies at which the 95% confidence intervals do not overlap indicate statistically significant differences among the plots. (A) In the presence of TTX, neurons exhibit a weak MPO. (B,C) MPOs were not enhanced by bath application of 100 µM 4-AP (B) but were significantly enhanced by 500 µM 4-AP, with peak power at 4.9 Hz (C). (D) Application of forksolin, an activator of the c-AMP cascade, at 10 µM also enhanced a MPO with peak power at 4.8 Hz. (E) The MPO was significantly enhanced by a combination of 500 µM 4AP and 10 µM forskolin, with peak power greater than for either drug alone but occurring at a similar frequency. (F) The MPO observed in forskolin and 4-AP was completely abolished by coapplication of NiCl (500 µM) to block low-threshold calcium channels.

Figure 6.8: Forskolin and 4-AP modulation of the membrane potential oscillation were not mimicked by dideoxy-forskolin and TEA, respectively Figure 6.

8: Forskolin and 4-AP modulation of the membrane potential oscillation were not mimicked by dideoxy-forskolin and TEA, respectively. Intrinsic membrane oscillations of BLA principal neurons, held at -60 mV, in response to a steady depolarizing current injection with and without artificial IPSPs. (A) Shows typical small membrane oscillations in TTX during the depolarizing current injection. In the presence of 1 µM TTX, the introduction of IPSPs evoked a transient depolarizing deflection at the termination of each IPSP, but failed to unmask a MPO. (B) MPOs are not enhanced by application of TEA (500 µM). (C) The addition of 10 µM forskolin had a small enhancing effect on MPOs in the presence of TEA. (D) Application of the inactive isomer dideoxy-forskolin in the presence of 4-AP did not enhance the MPO as observed previously with forskolin.

Figure 6.9: Membrane potential oscillations in the BLA were bi-directionally modulated by the adenylyl cyclase signaling cascade Figure 6.

9: Membrane potential oscillations in the BLA were bi-directionally modulated by the adenylyl cyclase signaling cascade. Cumulative power spectra of intrinsic theta frequency MPOs in BLA principal neurons. Responses are plotted as mean (solid lines) and 95% confidence intervals (shaded regions). Frequencies at which the 95% confidence intervals do not overlap indicate statistically significant differences among the plots. (A) BAPTA-containing patch solutions disorganized the frequency tuning of 4-AP- and forskolin-induced MPOs. (B) Inhibiting PKA activation completely abolishes forskolin-induced MPOs. (C) Activation of PKA with the cAMP analog 8Br-cAMP induces MPOs in TTX alone that are similar to those observed in response to forskolin. (D) Activation of mGluR II glutamate receptors with LY379268 completely blocked 4-AP and forskolin-induced theta MPOs.

Chapter 7: Discussion

7.1 Summary of Results The work presented here represents three major contributions to the state of knowledge concerning the function and development of the amygdala: 1) supporting a novel function of the neurotransmitter GABA in the BLA to facilitate network activation, 2) providing the first evidence that BLA neurons and GABAergic transmission are physiologically distinct in juveniles and adults, and 3) identifying effects of prenatal stress on the developmental trajectory of the BLA, including GABAergic transmission, that may underlie the conferred risk for psychiatric illness. The results of the studies on the normative development of BLA physiology and morphology are summarized in Figure 7.1.

In terms of GABAergic function in the adult BLA, we hypothesized that BLA neurons rebounding from GABAergic inhibition would exhibit membrane potential oscillations that would regulate their action potential firing. We found that rhythmic inhibition, which is synchronized across BLA principal neurons, can coordinate the spiking within and across neurons.





Furthermore, we suggest that this coordinated firing is a mechanism utilized by the adult circuit for the generation of network oscillations. This novel mechanism should influence the way we conceptualize GABA in the BLA, because this neurotransmitter has been classically treated as a singular system that functions solely to dampen activity and suppress fear (Quirk and Gehlert, 2003; Ehrlich et al., 2009). Because rhythmic inhibition is driven by parvalbumin-expressing interneurons, these findings argue for heterogeneity of BLA interneurons that should influence how we understand the effects of neuromodulators in the BLA. Considering the BLA circuit in terms of its capacity to generate network oscillations, the developmental changes we report in the BLA circuit are likely of great consequence for BLA function. Implications are discussed in Section 7.2.2.

We observed a wealth of interrelated changes to BLA neurons during postnatal development. These changes, which often covered an order of magnitude or more, occur throughout a period of emotional development that includes the emergence of and transitions to many amygdala-dependent behaviors. We propose that the maturation of amygdala function and emotional behavior occurs downstream of the changes to individual BLA neurons and synaptic transmission during the first postnatal month, which include: extension and expansion of dendrites, an approximately 10-fold increase in dendritic spine density, large reductions in input resistance and membrane time constant, faster action potentials with more hyperpolarized thresholds, larger and faster afterhyperpolarizations, higher spike rates, higher resonance frequency and greater propensity to oscillate, shifting subunits of ion channels that contribute to intrinsic properties and oscillations, the emergence of inhibitory GABA and a feed-forward shunt of cortical inputs, faster synaptic GABA responses that do not exhibit short-term synaptic depression, and changes to GABAA receptor subunit expression.

As stated above, we also showed that PS alters the developmental trajectory of many of these properties and concomitantly perturbs emotional behavior. Specifically, BLA principal neurons in PS animals had a more hyperpolarized resting membrane potential and action potential threshold across all ages, received slower GABAergic PSCs in a specific window around P14, did not exhibit the typical slow IPSCs in adulthood, and had reduced excitability starting at P28.

Furthermore, PS reduced the expression of GABAA receptor α1 subunit mRNA across all ages, and by at least 2 fold starting at P17. Finally, PS animals exhibited reduced anxiety-like behavior in adulthood, a trend toward reduced anxiety-like behavior at P17, and a trend toward reduced sociability. These effects of PS are consistent with many findings or models of amygdala deficits in autism spectrum disorders and schizophrenia, suggesting perturbation of BLA development following PS contributes to the etiology of neurodevelopmental disorders.

7.2 Integration of Findings 7.2.1 Importance of Studying Developmental Trajectories Neuroconstructivist theory suggests that brain function, genes, and environmental factors actively interact to shape brain development (Karmiloff-Smith, 2009). While a very simplistic and intuitive idea, the consequences can be profound and easily overlooked. For instance, researchers have long attempted to study neurodevelopmental disorders from the perspective of the adult brain, generally unsuccessfully. As Insel contends, the last century has seen little change in the prevalence or societal burden of mental illness, all the while diseases including tuberculosis and leprosy have seen great advances in treatment. One explanation for the relative difficulty in pinpointing the pathology and etiology of these disorders is that their neurodevelopmental basis adds many layers of complexity (2010). The classical (and understandably necessary) way of initially approaching neural function, where brain regions are modular and relatively insular (Karmiloff-Smith, 2009), is now outdated and has probably contributed to this stagnation.

Our findings of marked developmental change to BLA neurons support the idea that the amygdala is not a single module – for instance, a “fear center” – but likely has distinct functions throughout development. These changes occur at the precise ages when disorders like anxiety, depression, autism, and schizophrenia are thought to be instantiated, at least in part. Therefore, understanding the normative trajectory is an absolute necessity for identifying where perturbations arise and how they contribute to disease onset.

The findings we present on the effects of PS on amygdala development perfectly illustrate the importance of studying developmental trajectories. We identified a number of transient changes and precise ages of onset for alterations due to prenatal stress. These include a change to GABAergic transmission that came and went completely within a 7 day window from P10 to P17, and a shift in GABA receptor gene expression from a reduction of approximately 20% at P14 to nearly 60% by P17. Such a thorough examination of developmental trajectories was required to gain this level of precision in detection. Furthermore, had we not started with a systematic characterization of normative development of the brain systems of interest, we would not have been able to focus on windows of highest plasticity that are likely most vulnerable to perturbation. Without the thorough analysis employed here, we would have less precise knowledge regarding ages of onset for the effects of PS, and may have completely overlooked the transient change in GABAergic transmission around P14.

Section 1.4.

1 outlines a number of changes to the amygdala cause by PS, a number of which were only measured in adulthood. While changes to the adult system provide a valuable starting point, it is extremely difficult to build a working model of how these changes – for instance, increased density of PV+ interneurons – influences adult amygdala function, when developmental processes may be altered. An important future direction will be to apply thorough detection methods during early development for effects of early life risk factors only observed in adulthood, to better identify when changes occur. However, there will still be limitations to interpretation until we better understand how relevant neural systems function in the immature brain.

7.2.2 Potential Impact of Prenatal Stress on Emotion Via Amygdala Network Oscillations In Section 1.2.3.2 we described a number of studies implicating network oscillations in the BLA in emotional processing. The findings presented in Chapter 6 illustrate how GABA in the BLA may contribute to the generation of network oscillations, through interactions with intrinsic oscillations in BLA neurons. Interestingly, many aspects of the BLA circuit that contribute to the GABA-oscillation interaction are altered in the immature BLA and exhibit convergent maturation. For instance, spontaneous membrane potential oscillations become much more prominent around P21, reflecting changes to active membrane currents that likely also drive the concurrent shift of resonance frequency into the adult range, and the frequency of BLA network oscillations expressed during fear (Section 2.5.2).

Around the same time, the GABAergic circuit is becoming refined. PV+ interneurons, which provide the synchronized, rhythmic inhibition that coordinates BLA principal neurons, are first detected in the BLA around the same age (Berdel and Morys, 2000). In Section 4.4.3, we showed that GABAA receptors first become inhibitory around P14, suggesting that at younger ages the activity of interneurons would not be able to provide the requisite inhibition to enable a rebound and enhance neuronal oscillations. Furthermore, GABAA receptor-mediated currents become faster from P14 to P21 (Section 4.4.2). The kinetics of individual IPSCs should influence their effect on spike timing (Pouille and Scanziani, 2001) and are known to regulate the ability of GABAergic afferents to entrain postsynaptic oscillations (Tamas et al., 2004). Therefore, the near simultaneous shift towards faster, more inhibitory IPSCs with the emergence of oscillatory properties in BLA principal neurons represents both sides of the circuit assuming their mature properties, becoming able to promote network oscillations. In support of this model, no discernible network oscillations were observed in the BLA from birth through P14 in an electroencephalography study (Snead and Stephens, 1983). Prominent oscillations emerge by P14 age in other regions including cortex, hippocampus and thalamus, suggesting network oscillations in the BLA develop relatively late, driven by the maturation of BLA neurons and GABAergic transmission.



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