Ryan D. Darling

Theta-Contingent Trial Presentation Accelerates Learning Rate and Enhances Hippocampal Plasticity During Trace Eyeblink Conditioning

Hippocampal theta activity has been established as a key predictor of acquisition rate in rabbit (Orcytolagus cuniculus) classical conditioning. The current study used an online brain--computer interface to administer conditioning trials only in the explicit presence or absence of spontaneous theta activity in the hippocampus-dependent task of trace conditioning. The findings indicate that animals given theta-contingent training learned significantly faster than those given nontheta-contingent training. In parallel with the behavioral results, the theta-triggered group, and not the nontheta-triggered group, exhibited profound increases in hippocampal conditioned unit responses early in training. The results not only suggest that theta-contingent training has a dramatic facilitory effect on trace conditioning but also implicate theta activity in enhancing the plasticity of hippocampal neurons.

Eyeblink conditioning contingent on hippocampal theta enhances hippocampal and medial prefrontal responses

Trace eyeblink classical conditioning (tEBCC) can be accelerated by making training trials contingent on the naturally generated hippocampal 3- to 7-Hz theta rhythm. However, it is not well-understood how the presence (or absence) of theta affects stimulus-driven changes within the hippocampus and how it correlates with patterns of neural activity in other essential trace conditioning structures, such as the medial prefrontal cortex (mPFC). In the present study, a brain-computer interface delivered paired or unpaired conditioning trials to rabbits during the explicit presence (T(+)) or absence (T(-)) of theta, yielding significantly faster behavioral learning in the T(+)-paired group. The stimulus-elicited hippocampal unit responses were larger and more rhythmic in the T(+)-paired group. This facilitation of unit responses was complemented by differences in the hippocampal local field potentials (LFP), with the T(+)-paired group demonstrating more coherent stimulus-evoked theta than T(-)-paired animals and both unpaired groups. mPFC unit responses in the rapid learning T(+)-paired group displayed a clear inhibitory/excitatory sequential pattern of response to the tone that was not seen in any other group. Furthermore, sustained mPFC unit excitation continued through the trace interval in T(+) animals but not in T(-) animals. Thus theta-contingent training is accompanied by 1) acceleration in behavioral learning, 2) enhancement of the hippocampal unit and LFP responses, and 3) enhancement of mPFC unit responses. Together, these data provide evidence that pretrial hippocampal state is related to enhanced neural activity in critical structures of the distributed network supporting the acquisition of tEBCC.

Perinatal Citalopram Exposure Selectively Increases Locus Ceruleus Circuit Function in Male Rats

Selective serotonin reuptake inhibitors (SSRIs), such as citalopram (CTM), have been widely prescribed for major depressive disorder, not only for adult populations, but also for children and pregnant mothers. Recent evidence suggests that chronic SSRI exposure in adults increases serotonin (5-HT) levels in the raphe system and decreases norepinephrine (NE) locus ceruleus (LC) neural activity, suggesting a robust opposing interaction between these two monoamines. In contrast, perinatal SSRI exposure induces a long-lasting downregulation of the 5-HT-raphe system, which is opposite to that seen with chronic adult treatment. Therefore, the goal of the present investigation was to test the hypothesis that perinatal CTM exposure (20 mg/kg/d) from postnatal day 1 (PN1) to PN10 leads to hyperexcited NE-LC circuit function in adult rats (>PN90). Our single-neuron LC electrophysiological data demonstrated an increase in spontaneous and stimulus-driven neural activity, including an increase in phasic bursts in CTM-exposed animals. In addition, we demonstrated a corresponding immunoreactive increase in the rate-limiting catalyzing catecholamine enzyme (tyrosine hydroxylase) within the LC and their neocortical target sites compared to saline controls. Moreover, these effects were only evident in male exposed rats, suggesting a sexual dimorphism in neural development after SSRI exposure. Together, these results indicate that administration of SSRIs during a sensitive period of brain development results in long-lasting alterations in NE-LC circuit function in adults and may be useful in understanding the etiology of pervasive developmental disorders such as autism spectrum disorder.

Neonatal citalopram exposure decreases serotonergic fiber density in the olfactory bulb of male but not female adult rats

Manipulation of serotonin (5HT) during early development has been shown to induce long-lasting morphological changes within the raphe nuclear complex and serotonergic circuitry throughout the brain. Recent studies have demonstrated altered raphe-derived 5HT transporter (SERT) immunoreactive axonal expression in several cortical target sites after brief perinatal exposure to selective 5HT reuptake inhibitors such as citalopram (CTM). Since the serotonergic raphe nuclear complex projects to the olfactory bulb (OB) and perinatal 5HT disruption has been shown to disrupt olfactory behaviors, the goal of this study was to further investigate such developmental effects in the OB of CTM exposed animals. Male and female rat pups were exposed to CTM from postnatal day 8–21. After animals reach adulthood (>90 days), OB tissue sections were processed immunohistochemically for SERT antiserum. Our data revealed that the density of the SERT immunoreactive fibers decreased ~40% in the OB of CTM exposed male rats, but not female rats. Our findings support a broad and long-lasting change throughout most of the 5HT system, including the OB, after early manipulation of 5HT. Because dysfunction of the early 5HT system has been implicated in the etiology of neurodevelopmental disorders such as autism spectrum disorders (ASDs), these new findings may offer insight into the abnormal olfactory perception often noted in patients with ASD.

Altered Cerebellar Organization and Function in Monoamine Oxidase A Hypomorphic Mice

Monoamine oxidase A (MAO-A) is the key enzyme for the degradation of brain serotonin (5-hydroxytryptamine, 5-HT), norepinephrine (NE) and dopamine (DA). We recently generated and characterized a novel line of MAO-A hypormorphic mice (MAO-A(Neo)), featuring elevated monoamine levels, social deficits and perseverative behaviors as well as morphological changes in the basolateral amygdala and orbitofrontal cortex. Here we showed that MAO-A(Neo) mice displayed deficits in motor control, manifested as subtle disturbances in gait, motor coordination, and balance. Furthermore, magnetic resonance imaging of the cerebellum revealed morphological changes and a moderate reduction in the cerebellar size of MAO-A(Neo) mice compared to wild type (WT) mice. Histological and immunohistochemical analyses using calbindin-D-28k (CB) expression of Purkinje cells revealed abnormal cerebellar foliation with vermal hypoplasia and decreased in Purkinje cell count and their dendritic density in MAO-A(Neo) mice compared to WT. Our current findings suggest that congenitally low MAO-A activity leads to abnormal development of the cerebellum.

Behavioral training reverses global cortical network dysfunction induced by perinatal antidepressant exposure

Significance Cortical circuit miswiring underlying dysfunctional networks and aberrant behavior and distortions in modulatory control nuclei contributing to the regulation of learning, memory, and mood are hallmarks of autism. No available treatment effectively addresses these different dimensions of neurological distortion expressed in this disorder. Here, we show that a simple form of intensive auditory behavioral training in young adult rats resulted in a reversal of autistic-like neurological distortions expressed in the primary auditory cortex arising in an early postnatal epoch and also broadly improved the status of modulatory control processes expressing serotonin, dopamine, and noradrenaline. Abnormal cortical circuitry and function as well as distortions in the modulatory neurological processes controlling cortical plasticity have been argued to underlie the origin of autism. Here, we chemically distorted those processes using an antidepressant drug-exposure model to generate developmental neurological distortions like those characteristics expressed in autism, and then intensively trained altered young rodents to evaluate the potential for neuroplasticity-driven renormalization. We found that young rats that were injected s.c. with the antidepressant citalopram from postnatal d 1–10 displayed impaired neuronal repetition-rate following capacity in the primary auditory cortex (A1). With a focus on recovering grossly degraded auditory system processing in this model, we showed that targeted temporal processing deficits induced by early-life antidepressant exposure within the A1 were almost completely reversed through implementation of a simple behavioral training strategy (i.e., a modified go/no-go repetition-rate discrimination task). Degraded parvalbumin inhibitory GABAergic neurons and the fast inhibitory actions that they control were also renormalized by training. Importantly, antidepressant-induced degradation of serotonergic and dopaminergic neuromodulatory systems regulating cortical neuroplasticity was sharply reversed. These findings bear important implications for neuroplasticity-based therapeutics in autistic patients.

Altered Expression of Tyrosine Hydroxylase in the Locus Coeruleus Noradrenergic System in Citalopram Neonatally Exposed Rats and Monoamine Oxidase A Knock Out Mice

In rodents, noradrenergic (NE) locus coeruleus (LC) neurons are well known to express tyrosine hydroxylase (TH) immunoreactivity. However, due to its very low enzyme activity, NE cortical fibers do not typically express TH immunoreactivity, thus dopamine‐β‐hydroxylase (DBH) immunoreactivity is commonly utilized as a marker for NE cortical fibers. In this study, we performed double and/or triple immunofluorescent staining using antibodies against TH, DBH, and/or norepinephrine transporter (NET) to investigate the altered NE TH expression of cortical fibers in citalopram (CTM)‐exposed rats and monoamine oxidase (MAO) A knock out (KO) mice. We have noted the following novel findings: (1) neonatal exposure to the selective serotonin reuptake inhibitor (SSRI) CTM enhanced NE TH immunoreactive fibers throughout the entire neocortex, and a few of them appeared to be hypertrophic; (2) slightly enhanced NE cortical TH immunoreactive fibers were also noted in MAO A KO mice, and many of them revealed varicosities compared with the rather smooth NE cortical TH immunoreactive fibers in wild‐type (WT) mice; (3) LC dendrites of MAO A KO mice exhibited beaded morphology compared with the smooth LC dendrites in WT mice. Our findings suggest that both genetic and environmental factors during early development may play a critical role in the regulation and proper function of NE TH expression in the neocortex. Anat Rec, 2011.

Pretrial hippocampal θ-state differentiates single-unit response profiles during rabbit trace eyeblink conditioning

Eyeblink conditioning given in the explicit presence of hippocampal θ results in accelerated learning and enhanced multiple-unit responses, with slower learning and suppression of unit activity under non-θ conditions. Recordings from putative pyramidal cells during θ-contingent training show that pretrial θ-state is linked to the probability of firing increases versus decreases rather than to the magnitude of such responses. These findings suggest that the learning facilitation during θ may be due to the recruitment of additional neurons that increase their firing rate during trials.