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The cholinergic system has consistently been implicated in Pavlovian fear conditioning. Considerable work has been done to localize specific nicotinic receptor subtypes in the hippocampus and determine their functional importance; however, the specific function of many of these subtypes has yet to be determined. An alpha7 nicotinic antagonist methyllycaconitine (MLA) (35 microg), and a broad spectrum non-alpha7 nicotinic antagonist mecamylamine (35 microg) was injected directly into the dorsal hippocampus or overlying cortex either 15 min pre-, 1 min post-, or 6h post-fear conditioning. One week after conditioning, retention of contextual and cue (tone) conditioning were assessed. A significant impairment in retention of contextual fear was observed when mecamylamine was injected 15 min pre- and 1 min post-conditioning. No significant impairment was observed when mecamylamine was injected 6h post-conditioning. Likewise, a significant impairment in retention of contextual fear was observed when MLA was injected 1 min post-conditioning; however, in contrast, MLA did not show any significant impairments when injected 15 min pre-conditioning, but did show a significant impairment when injected 6h post-conditioning. There were no significant impairments observed when either drug was injected into overlying cortex. No significant impairments were observed in cue conditioning for either drug. In general, specific temporal dynamics involved in nicotinic receptor function were found relative to time of receptor dysfunction. The results indicate that the greatest deficits in long-term retention (1 week) of contextual fear are produced by central infusion of MLA minutes to hours post-conditioning or mecamylamine within minutes of conditioning.
The corticotrophin-releasing hormone (CRH) system integrates the stress response and is associated with stress-related psychopathology. Previous reports have identified interactions between childhood trauma and sequence variation in the CRH receptor 1 gene (CRHR1) that increase risk for affective disorders. However, the underlying mechanisms that connect variation in CRHR1 to psychopathology are unknown. To explore potential mechanisms, we used a validated rhesus macaque model to investigate association between genetic variation in CRHR1, anxious temperament (AT) and brain metabolic activity. In young rhesus monkeys, AT is analogous to the childhood risk phenotype that predicts the development of human anxiety and depressive disorders. Regional brain metabolism was assessed with (18)F-labeled fluoro-2-deoxyglucose (FDG) positron emission tomography in 236 young, normally reared macaques that were also characterized for AT. We show that single nucleotide polymorphisms (SNPs) affecting exon 6 of CRHR1 influence both AT and metabolic activity in the anterior hippocampus and amygdala, components of the neural circuit underlying AT. We also find evidence for association between SNPs in CRHR1 and metabolism in the intraparietal sulcus and precuneus. These translational data suggest that genetic variation in CRHR1 affects the risk for affective disorders by influencing the function of the neural circuit underlying AT and that differences in gene expression or the protein sequence involving exon 6 may be important. These results suggest that variation in CRHR1 may influence brain function before any childhood adversity and may be a diathesis for the interaction between CRHR1 genotypes and childhood trauma reported to affect human psychopathology.
This article presents an overview of ways to think about the brain and emotion and consider the role of evolution and expression in shaping the neural circuitry of affective processing. Issues pertaining to whether there are separate unique neural modules hard-wired for emotion processing or whether affective processing uses more generalized circuitry are considered. Relations between affect and cognition--specifically, memory--are examined from the perspective of overlapping neural systems. The role of individual differences in neural function in affective style are discussed, and the concepts of affective chronometry, or the time course of emotional responding and emotion regulation, are introduced. Finally, the extent to which certain emotional traits can be viewed as trainable skills is considered, and the relevance of work on neural plasticity to the skill framework is addressed. Data from a variety of sources using different types of measures is brought to bear on these questions, including neuroimaging and psychophysiological measures, studies of individuals of different ages ranging from early childhood to old age, studies of nonhuman primates, and observations of patients with localized brain damage. Emotions are viewed as varying in both type and dimension. Honoring brain circuitry in parsing the domain of affects will result in distinctions and differentiations that are not currently incorporated in traditional classification schemes.
PET imaging of the neuroreceptor systems in the brain has earned a prominent role in studying normal development, neuropsychiatric illness and developing targeted drugs. The dopaminergic system is of particular interest due to its role in the development of cognitive function and mood as well as its suspected involvement in neuropsychiatric illness. Nonhuman primate animal models provide a valuable resource for relating neurochemical changes to behavior. To facilitate comparison within and between primate models, we report in vivo D2/D3 binding in a large cohort of adolescent rhesus monkeys. METHODS: In this work, the in vivo D2/D3 dopamine receptor availability was measured in a cohort of 33 rhesus monkeys in the adolescent stage of development (3.2-5.3 years). Both striatal and extrastriatal D2/D3 binding were measured using [F-18]fallypride with a high resolution small animal PET scanner. The distribution volume ratio (DVR) was measured for all subjects and group comparisons of D2/D3 binding among the cohort were made based on age and sex. Because two sequential studies were acquired from a single [F-18]fallypride batch, the effect of competing (unlabeled) ligand mass was also investigated. RESULTS: Among this cohort, the rank order of regional D2/D3 receptor binding did not vary from previous studies with adult rhesus monkeys, with: putamen>caudate>ventral striatum>amygdala approximately substantia nigra>medial dorsal thalamus>lateral temporal cortex approximately frontal cortex. The DVR coefficient of variation ranged from 14%-26%, with the greatest variance seen in the head of the caudate. There were significant sex differences in [F-18]fallypride kinetics in the pituitary gland, but this was not observed for regions within the blood-brain barrier. Furthermore, no regions in the brain showed significant sex or age related differences in DVR within this small age range. Based on a wide range of injected fallypride mass across the cohort, significant competition effects could only be detected in the substantia nigra, thalamus, and frontal cortex, and were not evident above intersubject variability in all other regions. CONCLUSION: These data represent the first report of large cohort in vivo D2/D3 dopamine whole brain binding in the adolescent brain and will serve as a valuable comparison for understanding dopamine changes during this critical time of development and provide a framework for creating a dopaminergic biochemical atlas for the rhesus monkey.
Pseudoneglect is traditionally viewed as reflecting right hemisphere specialization for processing spatial information, resulting in orienting toward the contralateral, left, hemispace. Recent evidence suggests that healthy individuals differ from each other in both direction and magnitude of orienting bias, and moreover, the bias displayed by a person is consistent across time, suggesting that it may represent a trait of the individual. Animal studies reveal consistent orienting bias within an individual, which reflects asymmetry in dopaminergic brain systems. We measured basal D2-like receptor binding using positron emission tomography and the high-affinity ligand [F-18]fallypride, to test the hypothesis that asymmetry in dopaminergic neurotransmission in healthy humans modulates the orienting bias in humans. As predicted, we found that individual differences in the direction and magnitude of the orienting bias were strongly associated with the pattern of asymmetric binding of dopamine (DA) D2 receptors in the striatum, as well as clusters in the frontal and temporal cortex. These findings show for the first time that orienting bias reflects individual differences in the lateralization of DA systems in the healthy human brain.
Regional modulation of the level of cortical neurotransmitters in the brain would serve as a new functional brain mapping technique to interrogate the neurochemical actions of the brain. We investigated the utility of the application of low-intensity, pulsed sonication of focused ultrasound (FUS) to the brain to modulate the extracellular level of dopamine (DA) and serotonin (5-HT). FUS was delivered to the thalamic areas of rats, and extracellular DA and 5-HT were sampled from the frontal lobe using the microdialysis technique. The concentration changes of the sampled DA and 5-HT were measured through high-performance liquid chromatography. We observed a significant increase of the extracellular concentrations of DA and 5-HT in the FUS-treated group as compared with those in the unsonicated group. Our results provide the first direct evidence that FUS sonication alters the level of extracellular concentration of these monoamine neurotransmitters and has a potential modulatory effect on their local release, uptake, or degradation. Our findings suggest that the pulsed application of FUS offers new perspectives for a possible noninvasive modulation of neurotransmitters and may have diagnostic as well as therapeutic implications for DA/5-HT-mediated neurological and psychiatric disorders. © 2011 Wiley Periodicals, Inc. Int J Imaging Syst Technol, 21, 232–240, 2011
Lesions of the dorsal hippocampus have been shown to disrupt both the acquisition and the consolidation of memories associated with contextual fear (fear of the place of conditioning), but do not affect fear conditioning to discrete cues (e.g., a tone). Blockade of central muscarinic cholinergic receptor activation results in selective acquisition deficits of contextual fear conditioning, but reportedly has little effect on consolidation. Here we show for the first time that direct infusion of the muscarinic cholinergic receptor antagonist, scopolamine, into the dorsal hippocampus produces a dose-dependent deficit in both acquisition and consolidation of contextual fear conditioning, while having no impact on simple tone conditioning.
Our outside world changes continuously, for example, when driving through traffic. An important question is how our brain deals with this constant barrage of rapidly changing sensory input and flexibly selects only newly goal-relevant information for further capacity-limited processing in working memory. The challenge our brain faces is experimentally captured by the attentional blink (AB): an impairment in detecting the second of two target stimuli presented in close temporal proximity among distracters. Many theories have been proposed to explain this deficit in processing goal-relevant information, with some attributing the AB to capacity limitations related to encoding of the first target and others assigning a critical role to on-line selection mechanisms that control access to working memory. The current study examined the role of striatal dopamine in the AB, given its known role in regulating the contents of working memory. Specifically, participants performed an AB task and their basal level of dopamine D2-like receptor binding was measured using PET and [F-18]fallypride. As predicted, individual differences analyses showed that greater D2-like receptor binding in the striatum was associated with a larger AB, implicating striatal dopamine and mechanisms that control access to working memory in the AB. Specifically, we propose that striatal dopamine may determine the AB by regulating the threshold for working memory updating, providing a testable physiological basis for this deficit in gating rapidly changing visual information. A challenge for current models of the AB lies in connecting more directly to these neurobiological data.
Subregional analyses of the hippocampus have suggested a selective role for the CA1 subregion in intermediate/long-term spatial memory and consolidation, but not short-term acquisition or encoding processes. It remains unclear how the direct cortical projection to CA1 via the perforant path (pp) contributes to these CA1-dependent processes. It has been suggested that dopamine selectively modulates the pp projection to CA1 while having little to no effect on the Schaffer collateral (SC) projection to CA1. This series of behavioral and electrophysiological experiments takes advantage of this pharmacological dissociation to demonstrate that the direct pp inputs to CA1 are critical in CA1-dependent intermediate-term retention and retrieval function. Here we demonstrate that local infusion of the nonselective dopamine agonist, apomorphine (10, 15 microg), into the CA1 subregion of awake animals produces impairments in between-day retention and retrieval, sparing within-day encoding of a modified Hebb-Williams maze and contextual conditioning of fear. In contrast, apomorphine produces no deficits when infused into the CA3 subregion. To complement the behavioral analyses, electrophysiological data was collected. In anesthetized animals, local infusion of the same doses of apomorphine significantly modifies evoked responses in the distal dendrites of CA1 following angular bundle stimulation, but produces no significant effects in the more proximal dendritic layer following stimulation of the SC. These results support a modulatory role for dopamine in the EC-CA1, but not CA3-CA1 circuitry, and suggest the possibility of a more fundamental role for EC-CA1 synaptic transmission in terms of intermediate-term, but not short-term spatial memory.