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The amplitude of Ih may be regulated throughout the first postnatal month to homeostatically maintain a consistent resting membrane potential. There are, however, visible changes in the voltage waveform of Ih because of faster Ih activation and τmemb. Changes to Ih in the BLA may be due to transitions in the expression of subtypes of HCN, the channel mediating Ih, as in thalamic and hippocampal neurons (Bender et al., 2001; Kanyshkova et al., 2009). Ih activation kinetics were assessed by fitting the Cs+ subtraction current with a two-term exponential equation at P14, P21, and P28, since Ih has previously been shown to have two distinct activation time constants (Pena et al., 2006). It is not clear why Ih at P7 appeared to have only a single activation time constant. While Cs+ is not selective for HCN channels, we believe the subtraction currents are largely comprised of Ih. The hyperpolarization-activated current we observed likely involved activation of voltage-gated K+ channels, which can also be sensitive to Cs+. However, for Cs+ to affect those channels, it must enter the cell, which is unlikely at the voltages used for this protocol. Assessed by blockade with Cs+, Ih makes a substantial contribution to resonance as early as P14. From P14 to P28, Cs+ shifted the peak resonance toward lower frequencies, but at P7, there was little impact. Interestingly, the greatest effects on resonance of Ih blockade were seen at P14, when the resonance in Cs+ resembled that seen at P7 in control conditions. This suggests Ih emerges as a major contributor to resonance between P7 and P14. Starting at P21, Cs+ did not functionally abolish resonance by enhancing power preferentially in the lowest frequencies, as it did at P14. Cs+ application had a diminishing effect on resonance with age following P14, suggesting other currents begin to play a greater role in shaping resonance. Although the amplitude of Ih continues to increase beyond P14, the concurrent reduction of input resistance and the compensatory effect of other emerging currents may mitigate the effects of Cs+ application on resonance.

Considering the unique role Ih plays in shaping resonance at P14, at that age we expect profound sensitivity of resonance to neuromodulators that influence cAMP, a classic modulator of Ih. Developmental changes in neuromodulators contribute to maturation of Ih around P14 in the medial superior olive, further suggesting neuromodulation is relevant for neuronal function at that age (Khurana et al., 2012). Interestingly, Ih conductance in BLA principal neurons is reduced by the anxiolytic neurotransmitter neuropeptide Y and enhanced by the anxiogenic neurotransmitter corticotrophin-releasing factor (Giesbrecht et al., 2010).

Changes to resonance due to blockade of Ih are indirect and largely attributable to effects on τmemb. There is a close relationship between τmemb and peak resonance frequency (Hutcheon and Yarom, 2000), and the magnitude of resonance is linearly correlated with Ih amplitude (Marcelin et al., 2012). We showed that blockade of Ih directly impacts τmemb but does not maintain the fitted relationship between τmemb and peak resonance frequency, suggesting that, aside from passively contributing to resonance through τmemb, Ih contributes actively through its voltage-dependence and activation kinetics. In hippocampal pyramidal neurons, the amplitude of Ih is tightly correlated with the magnitude of the resonance peak (Marcelin et al., 2012).

2.5.4 Maturation of trains of action potentials As expected, trains of action potentials elicited by direct current injection changed qualitatively across the first postnatal month. At P7, neurons exhibited a consistent action potential frequency throughout trains; as the animals aged, the frequency of the first two to three spikes increased dramatically, such that mature cells exhibited doublets or triplets at the onset of firing. Spike doublets have been documented in adult neurons of the basolateral (Rainnie et al.,

1993) and lateral (Driesang and Pape, 2000) nuclei of the amygdala, and are thought to improve the fidelity of synaptic transmission (Lisman, 1997). Furthermore, doublets have been suggested to promote network oscillations and bridge the temporal gap between inputs to the amygdala representing conditioned and unconditioned stimuli during fear conditioning (Driesang and Pape, 2000). Interestingly, changes in dendritic morphology can directly affect spiking properties, including doublet firing (Mainen and Sejnowski, 1996), and experiments are underway to characterize morphological changes in these neurons during development.

In this study, maximal firing rate reached maturity in P14 cells, while in cortical pyramidal neurons, maximal firing rates have been reported to reach mature values as early as P2 (McCormick and Prince, 1987). This disparity is consistent with the late development of emotional processing relative to sensorimotor processing. The consistency of firing rates after P14 may be afforded by strengthening of IA through insertion of Kv4 channels into the membrane (Vacher et al., 2006) to compensate for reduced medium afterhyperpolarizations (mAHPs).

It is important to note that, while spike trains elicited with square current pulses were relatively consistent across the first postnatal month, there were profound changes in the spontaneous activity of neurons depolarized to near threshold with direct current. Specifically, neurons at P7 exhibited highly erratic membrane potentials characterized by waves of depolarization, likely involving activation of low-threshold calcium currents, which resulted in bursts of action potentials and periods of quiescence. Throughout the first postnatal month, membrane potentials became more stable near threshold. It is possible that the erratic membrane potentials in immature neurons were due to instability of the seal or physical qualities of the membrane. This is likely not the case based on the high Rin and repetitive firing exhibited at P7, properties indicative of a healthy membrane and seal. Furthermore, the membrane potential at P7 was stabilized by application of TTX (unpublished observation), suggesting the volatility was introduced by synaptic or intrinsic currents.

2.5.5 Maturation of action potentials and AHPs There were also many developmental changes to properties of individual action potentials, including threshold, kinetics, and AHPs. Action potential threshold hyperpolarized until P21, potentially counteracting the effects of reduced Rin on neuronal excitability and acting to maintain consistent firing activity. The value we report for mature threshold (-41 mV) differed from the threshold values previously reported for mature BLA principal neurons (mean of -52 mV, (Rainnie et al., 1993), but this difference may be due to methods of recording (whole-cell patch vs. sharp) or analysis. Action potentials rise-time, decay-time and half-width were halved from P7 to P28, with the majority of change occurring by P21. Thalamic neurons also achieve mature action potential durations around P21 (Ramoa and McCormick, 1994), while neocortical projection neurons do so somewhat earlier, at approximately P14 (McCormick and Prince, 1987).

Faster action potentials would allow for faster firing rates and may also impact calcium influx due to spiking, which could impact AHPs of action potentials.

Across the first postnatal month, AHPs matured in two ways: mAHPs became significantly faster and shallower while fast AHPs (fAHPs) became faster and deeper. Fast AHPs were not present at P7 but were present in two thirds of neurons by P21, when they exhibited adult-like waveforms. The emergence of fAHPs corresponds with faster action potential repolarization, and these phenomena are likely both due to maturation of fast voltage-gated potassium currents. A reduction in mAHP duration across the first postnatal month has also been observed in entorhinal cortex (Burton et al., 2008). Medium AHPs can normalize inter-spike intervals and promote regular firing, hindering temporal coding mechanisms in favor of rate coding (Prescott and Sejnowski, 2008); smaller mAHPs in adult principal neurons are therefore another factor, along with smaller τmemb and more prominent oscillations, that could promote temporal coding in mature emotional processing. Both fAHPs and mAHPs have been reported in adult BLA principal neurons (Rainnie et al., 1993), and the reported values suggest the trends we observed in AHP amplitude and duration continue past P28. A subset of adult BLA principal neurons has been shown to also express a slow AHP (Rainnie et al., 1993; Faber and Sah, 2002).

Unfortunately, we were unable to assess the presence of a sAHP in immature BLA principal neurons with our data set. Future studies should address whether the presence of a sAHP emerges during postnatal development, as this could shed light on the developmental differentiation of principal neuron subtypes.

The trajectory of fAHP maturation corresponds with a reduction of the first inter-spike interval, such that almost all neurons at P28 have a fAHP and fire doublets. Interestingly, reduction of fAHP amplitude in the lateral amygdala through modulation of BK channels has been shown following stress and linked to anxiety (Guo et al., 2012), suggesting doublets are relevant for amygdala function. While the emergence of a fAHP likely involves changes in currents like BK, we cannot make any direct claims regarding the quantity or quality of underlying currents because we measured voltage deflections. Furthermore, because these voltage deflections are measured relative to action potential threshold, which is itself changing across development, the interaction of AHPs with currents regulating inter-spike interval may vary with age.

2.5.6 Maturation of amygdala connectivity and neuronal morphology The BLA contributes to a network of brain regions that produce and regulate emotional behavior, including the prefrontal cortex, which itself develops substantially during the first postnatal month (Van Eden and Uylings, 1985; Bourgeois et al., 1994; Anderson et al., 1995;

Rakic, 1995; Gourley et al., 2012). Afferents from cortical areas, including the prefrontal and auditory cortices, do not emerge in the BLA until around P13, while thalamic afferents are present as early as P7 (Bouwmeester et al., 2002b). Interestingly, a functional interaction of the prefrontal cortex and BLA also develops late; the medial prefrontal cortex does not contribute to extinction learning until P24 (Kim et al., 2009).

The interaction of the BLA with other brain regions that process emotion depends on the function BLA principal neurons. We have provided evidence that neurons of the BLA are not physiologically mature at birth, and have argued that postnatal changes in amygdala function and emotional processing are likely driven by drastic changes to the physiology of amygdala neurons.

These physiological changes may be driven by developmental changes to the morphology or ion channel expression of these neurons. Changes to the size of the soma or extent of dendritic arborization can alter the electrophysiological properties of neurons. In terms of ion channels, we described maturation in the BLA of the properties of Ih, which suggests there are concomitant changes to the underlying ion channels; in addition, many other currents shape the properties we have shown to mature in BLA principal neurons, suggesting a host of changes to gene expression during development.

Several studies have addressed these aspects of amygdala development. The BLA increases in volume from embryonic day 17 until P14 (Berdel et al., 1997b), although the total number of neurons reaches the mature value at P7. From birth to P7, the cross-sectional area of rat BLA neurons doubles, but at P7 the majority of neurons are still small and have only one or two main dendrites (Berdel et al., 1997a). By P14, the cross-sectional area is the same as in the adult. A 3-fold increase in total synapses in the BLA from P7 to P28, as measured by synaptophysin staining (Morys et al., 1998), probably reflects increased intrinsic connectivity as well as maturation of inputs to the amygdala. Interestingly, in terms of BLA volume and number of neurons, throughout development no differences were observed across sex (Rubinow and Juraska, 2009), corroborating our findings of no sex differences in principal neuron physiology.

Despite the number of studies addressing BLA neuron morphology during development, none have employed modern techniques to characterize dendritic arborization of estimate soma volume, necessary information to understand the factors driving the maturation of BLA neuron physiology and connectivity. Furthermore, the postnatal emergence of afferents from throughout the brain and the increase in synaptophysin staining suggest robust changes to the inputs to BLA neurons, which should be reflected not only in dendritic arborization but also in the expression of dendritic spines. In order to better identify how the amygdala circuit becomes organized and functions during postnatal development, we addressed the morphology and ion channel expression in this neuronal population throughout development. Our findings are summarized in Chapter 3.

Figure 2.1: Maturation of physiological properties of BLA principal neurons across the first postnatal month Figure 2.

1: Maturation of physiological properties of BLA principal neurons across the first postnatal month. Illustrated are representative voltage responses to a series of transient (1 s) hyperpolarizing and depolarizing current steps, depicting age-dependent changes in the active and passive membrane properties of BLA principal neurons. All neurons were held at -60 mV with direct current injection. The amplitudes of current injection were adjusted for each neuron to normalize the voltage deflections. Note the difference in scale for the current injections of the neurons depicted in the top panel (postnatal day 7 (P7, left) and 14 (right)) and those depicted in the bottom panel (P21 (left) and 28 (right)).

Figure 2.2: Input resistance and membrane time constant decrease with age Figure 2.

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