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the action potential half-width decreased between P7 and P28 (Figure 2.8C), with the value at each time-point being significantly faster than at the previous (p 0.01, Kruskal-Wallis with Wilcoxon rank sum post-hoc tests, χ25 = 217.8). The median half-width was 1.39 ms at P7 (n = 49), 1.23 ms at P10 (n = 35), 1.11 ms at P14 (n = 52), 0.90 ms at P21 (n = 44), 0.76 ms at P28 (n = 56), and 0.83 ms at P35 (n = 57). Action potential 10-90% rise-time also decreased over this window, but the change was more gradual (Figure 2.8D). Here, the median rise-time was 0.56 ms at P7 (n = 51), 0.47 ms at P10 (n = 37), 0.42 ms at P14 (n = 55), 0.37 ms at P21 (n = 45), 0.30 ms at P28 (n = 57), and 0.32 ms at P35 (n = 55). The only significant neighboring comparison in rise-time was between P21 and P28 (p 0.001, Kruskal-Wallis with Wilcoxon rank sum post-hoc tests, χ25 = 134.7), but every transition across two time-points was significant (p 0.001).

Finally, the 90-10% decay-time also decreased more than two-fold from P7 to P28 (Figure 2.8E) and decreased significantly between every neighboring pair of time-points aside from P10 to 14 (p 0.001, Kruskal-Wallis with Wilcoxon rank sum post-hoc tests, χ25 = 201.6). Here, the median decay-time was 1.64 ms at P7 (n =50), 1.30 ms at P10 (n = 36), 1.07 ms at P14 (n = 53), 0.83 ms at P21 (n = 43), 0.66 ms at P28 (n = 56), and 0.86 ms at P35 (n = 56). Development of Afterhyperpolarization The maturation of action potential duration strongly suggested that calcium influx due to individual spikes would also change significantly. Hence, we next examined the developmental expression of post-spike afterhyperpolarizations (AHPs), which have been shown to have some calcium-dependency in amygdala principal neurons (Faber and Sah, 2002) and could further contribute to the observed changes in spike trains. As expected, AHP expression also matured across the first postnatal month, with clear changes in both the fast and medium AHP (fAHP and mAHP, respectively). Figure 2.9A illustrates representative AHPs of BLA principal neurons at P7, 14, 21, and 28. As can be seen, the mAHP is already present at P7, whereas a distinct fAHP does not appear until P21. As shown in Figure 2.9B, the mAHP became faster and more shallow from P7 to P28, with times-to-peak of 91.4 ± 11.8 ms at P7 (n = 8), 69.0 ± 5.8 ms at P14 (n = 15),

59.8 ± 3.8 ms at P21 (n = 22), and 57.2 ± 3.6 ms at P28 (n = 42). The amplitude of the mAHP was -14.9 ± 2.4 mV at P7, -13.2 ± 1.9 mV at P14, -12.4 ± 2.6 mV at P21, and -11.1 ± 1.9 mV at P28. There was a significant effect of age on mAHP amplitude (p 0.001, One-way ANOVA, F3,83 = 8.95) and duration (p 0.01, Kruskal-Wallis, χ23 = 11.45). The fAHP emerged at P14 (Figure 2.9C), with 33% of neurons exhibiting a fAHP. The proportion increased to 68% by P21 and to 74% by P28. The fAHP became faster across this period, with times-to-peak (mean ± SEM) of 2.8 ± 0.1 ms at P14 (n = 5 of 15), 2.4 ± 0.1 ms at P21 (n = 15 of 22), and 2.4 ± 0.1 ms at P28 (n = 31 of 42). The fAHP also became deeper, with amplitudes (mean ± SD) of -2.8 ± 2.6 mV at P14, -5.2 ± 2.3 mV at P21, and -6.1 ± 3.1 mV at P28. The effect of age was not significant for fAHP amplitude (p = 0.052, One-way ANOVA, F2,48 = 3.147) and duration (p = 0.061, Kruskal-Wallis, χ22 = 5.61).

2.4.4 No Effect of Sex on Postnatal Changes in Physiological Properties Due to differences in emotional processing and development of emotional behaviors across sexes, there is great interest in sex differences in amygdala maturation. Therefore, we performed a statistical analysis to assess sex differences in many of the physiological properties discussed above. Using a two-way ANOVA with factors of age and sex, we compared groups of between 8 and 16 neurons per sex at P14, 21, and 28. We found no main effect of sex (p 0.05) in any of the parameters tested (Rin, τmemb, action potential threshold, half-width, 10-90% risetime, 90-10% decay-time, and first ISI). We conducted a post-hoc power analysis using G*Power (Faul et al., 2007) to assess whether we had sufficient power to detect an effect of sex.

The power to detect a large effect size (f = 0.40, Cohen, 1988) was 0.94, but the power to detect a medium-sized effect (f = 0.25) was 0.59. Therefore, we cannot rule out the possibility of an effect of sex on these parameters in development, but expect such an effect would not be large. It is important to note that all measures were taken before sexual maturity, and large effects of sex may emerge by adulthood.

2.5 Discussion In this study, we have provided the first evidence that physiological properties of principal neurons in the rat BLA undergo significant change during the first postnatal month.

Characterizing how neurons of the amygdala develop is fundamental to understanding normative emotional development and, in turn, how risk factors and genetic predispositions are translated into developmental emotional disorders like anxiety, depression, autism spectrum disorders, and schizophrenia (Pine, 2002; Kim-Cohen et al., 2003; Kessler et al., 2005; Monk, 2008). Emotional processing, in particular fear learning, is critically dependent on the BLA (Davis, 2000; LeDoux, 2000), and the rapid and robust changes to fear learning observed during the first postnatal month in rats suggest the BLA develops profoundly during this period (Campbell and Ampuero, 1985;

Moye and Rudy, 1987; Hunt et al., 1994; Sullivan et al., 2000; Kim and Richardson, 2007). To facilitate comparisons of the timing of our observations to milestones in other species, consider that an infant rat first opens its eyes and reaches comparable cortical maturity to a newborn human at around two weeks after birth, is weaned around three, and reaches sexual maturity between six and eight (Quinn, 2005). In our hands, BLA principal neurons exhibited the greatest physiological changes between P7 and P21. Furthermore, neuronal physiology at P28 very closely resembled that of neurons recorded after P35, as well as previous reports of adult BLA principal neurons. These findings suggest that the electrophysiological properties of neurons in the human amygdala may undergo the largest transitions before one year of age and continue to develop into early adolescence. All of these changes support the notion that the BLA and its contribution to emotional processing are in flux well into postnatal life, marking a period of vulnerability for the circuit and long-term emotional outcomes (Spear, 2009).

2.5.1 Maturation of passive membrane properties The most fundamental aspect of physiology in which we observed changes was passive membrane properties. For both input resistance (Rin) and membrane time constant (τmemb), a great proportion of maturation took place by P21. In fact, Rin decreased 6-fold and τmemb more than 3fold between P7 and P21. The values we report for Rin and τmemb at P28 and P35 match those reported previously for adult BLA principal neurons (Rainnie et al., 1993), suggesting these neurons are physiologically mature by P28. These trajectories are also comparable to those seen in sensorimotor (McCormick and Prince, 1987) and prefrontal cortex (Zhang, 2004) as well as thalamus (Ramoa and McCormick, 1994). The decreases in Rin and τmemb are consistent with the observed increase in cross-sectional area of BLA neurons (Berdel et al., 1997b) and likely involve insertion of ion channels into the membrane. The developmental reduction of Rin would, in isolation, reduce responsiveness to synaptic input, and may serve as a homeostatic mechanism to compensate for increasing synaptic strength, as seen elsewhere (Zhang, 2004). The larger τmemb in younger neurons means their voltage responses to synaptic input would be slower, promoting temporal summation of inputs. However, this would also reduce temporal precision of action potentials, meaning preadolescent amygdala neurons may be less able to coordinate action potentials and take advantage of temporal coding and spike-timing dependent plasticity.

2.5.2 Maturation of membrane potential oscillations and resonance Passive membrane properties like τmemb also help shape oscillatory properties of neurons, which influence the sensitivity of neurons to input and production of action potentials based on frequency. Over the first postnatal month, the proportion of BLA principal neurons expressing spontaneous membrane potential oscillations (MPOs) increased substantially and the frequency of those MPOs increased. Spontaneous MPOs are expressed in adult BLA principal neurons in the guinea pig at a proportion comparable to that seen here at P21 and P28 (Pape et al., 1998). The change in frequency with development was not significant, although similar trends have been observed in entorhinal cortex (Boehlen et al., 2010) and midbrain (Wu et al., 2001).

Interestingly, the MPO was abolished by application of 1 µM tetrodotoxin (unpublished observation), suggesting the oscillation is promoted by synaptic activity.

Maturation of intrinsic oscillatory activity in BLA principal neurons also manifests as a change in the preferred resonance frequency. Intrinsic resonance has a similar time-course of development to the MPO, expressing a mature phenotype in the BLA at P21. Resonance and MPOs also exhibit coordinated development in neurons of the entorhinal cortex (Burton et al., 2008; Boehlen et al., 2010). These two phenomena are mediated by a similar set of voltage-gated currents and have similar frequency preference (Lampl and Yarom, 1997; Hutcheon and Yarom, 2000; Erchova et al., 2004). The mean peak resonance frequency we report here for BLA principal neurons at P28, 5.69 Hz, differs substantially from those reported for the guinea pig, 2.5 Hz (Pape and Driesang, 1998), and the adult rat, 4.2 Hz (Chapter 6; Ryan et al., 2012). While these differences could be due to continued maturation of oscillatory properties after P28, we believe it is more likely due to differences in species or recording voltage, which is known to impact resonance (Pape and Driesang, 1998; Tseng and Nadim, 2010).

Spontaneous MPOs can directly influence spike timing (Desmaisons et al., 1999;

Richardson et al., 2003), and in our hands, action potentials were phase-locked with the peak of the spontaneous MPO in some neurons at P28. Oscillatory properties of individual neurons contribute to the production of network oscillations (Lampl and Yarom, 1997; Tohidi and Nadim, 2009), which are an important component of communication between distant brain regions (Engel et al., 2001; Singer, 2009; Canolty and Knight, 2010; Fujisawa and Buzsaki, 2011). Coherent oscillations are expressed by the amygdala and downstream target regions, including the hippocampus and prefrontal cortex, during fear acquisition and expression (Madsen and Rainnie, 2009; Sangha et al., 2009; Pape and Pare, 2010). Importantly, the frequency of these coherent oscillations overlaps with the frequency of peak resonance and spontaneous MPOs in BLA principal neurons at P28, suggesting the emergence of these properties contributes to the mature expression of fear. Theta oscillations in local field potentials from the hippocampus increase in frequency throughout the third and fourth postnatal weeks, corresponding with emergence of mature network properties (Wills et al., 2010). This finding further supports a role for development of the oscillatory properties of individual neurons in network function and mature behavior.

Considering the importance of oscillatory properties of individual neurons for the generation of network oscillations (Lampl and Yarom, 1997; Desmaisons et al., 1999; Richardson et al., 2003; Tohidi and Nadim, 2009), their emergence in the BLA should correspond with that of principal neuron resonance. Based on electroencephalograms of the developing rat brain, no discernible network oscillations are observed in the BLA from birth through P14. Prominent oscillations emerge by this age in other regions including cortex, hippocampus and thalamus (Snead and Stephens, 1983), suggesting network oscillations in the BLA develop relatively late.

We argue that network oscillations in the amygdala are promoted by organization of principal neuron MPOs by synaptic input from parvalbumin-expressing interneurons (Ryan et al., 2012).

Interestingly, these interneurons emerge in the BLA at P17 and reach mature expression by P21 (Berdel and Morys, 2000), when mature oscillatory properties would render BLA principal neurons more susceptible to organization by parvalbumin interneurons.

2.5.3 Maturation of Ih and its contribution to resonance The observed changes to resonance, as well as to passive membrane properties, were likely influenced by maturation of the voltage-sensitive current, Ih. This current is critically involved in the expression of resonance properties (Hutcheon et al., 1996a; Hu et al., 2002;

Marcelin et al., 2012) and contributes to input resistance at rest (Surges et al., 2004). Here we have shown an increase in amplitude and a decrease in activation time constant of Ih across the first postnatal month, as shown previously in other brain regions (Vasilyev and Barish, 2002;

Khurana et al., 2012). The interaction of a 7-fold increase in Ih current amplitude across this window with a nearly 10-fold reduction of Rin explains the fairly consistent amplitude of voltage sag at all ages. Consistent sag amplitude across the first postnatal month was also observed in entorhinal cortex despite increasing Ih conductance (Burton et al., 2008).

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