Altered functional connectivity of the amygdala in Crohn’s disease

Brain Imaging and Behavior - Crohn’s disease (CD), a chronic inflammatory bowel disease, involved in brain structural and functional changes, including the amygdala. Amygdala is a key...     

Neuritic degeneration in the hippocampus and amygdala in Parkinson’s disease in relation to Alzheimer pathology

It has been suggested that dystrophic neurites in the hippocampal CA2-3 sector are characteristic of diffuse Lewy body disease (DLBD) but not of Parkinson’s disease (PD). We investigated the severity of neuritic change in the CA2-3 sector of the hippocampus and in the periamygdaloid cortex (PAC) in 45 patients with clinically diagnosed and neuropathologically verified PD. Samples from amygdala, hippocampus, entorhinal cortex (ERC) and cortical gyri were examined for Alzheimer-type (AD) changes and Lewy bodies (LBs) using antibodies against ubiquitin and tau. Ubiquitin-positive but polyclonal tau-negative neurites were detected in the CA2-3 region of the hippocampus in 88% of patients and in the PAC in 91% of patients. The CA2-3 sector neurites correlated significantly only with LBs in all other brain areas, except in the amygdala. The neurites in the PAC correlated significantly with neuropathological variables in all other brain areas examined, except with tangles in the precentral and frontal gyrus and with LBs in the amygdala and in the ERC. Unlike in the CA2-3 sector, the neuritic change in the PAC was more prominent in those PD patients with more severe cognitive impairment (P = 0.03). There was no significant correlation between the apoɛ4 allele load and the neuritic change in the PAC or in the CA2-3 sector. Our study revealed that cortical LBs and neuritic change in the amygdala and hippocampal CA2-3 sector co-exist in PD. Unlike hippocampal neurites, the PAC neurites are related to AD pathology. There seems to be a relationship between the PAC neurites and cognitive impairment in PD, but its significance needs further elucidation. Received: 28 September 1998 / Revised: 4 January 1999 / Accepted: 5 January 1999     

Does the pineal gland play a role in neuroendocrine fear responses?

The pineal gland secretes melatonin under an influence of suprachiasmatic nucleus neurones. Pinealectomy or melatonin administration affects behavioural responses to novel stimuli. Fear or novel stimuli inhibit vasopressin (VP) and facilitate oxytocin (OT) or prolactin (PRL) release from the pituitary. Thus the suprachiasmatic nucleus-pineal gland system may modulate VP, OT and PRL responses to conditioned fear stimuli. In the present experiments with male rats, pinealectomy or melatonin administration did not significantly change VP, OT or PRL responses to conditioned fear stimuli. Electrolytic lesions of the suprachiasmatic nuclei impaired VP but not OT or PRL responses. The results show that the pineal gland is not involved in neuroendocrine responses to conditioned fear stimuli and suggest that the suprachiasmatic nucleus is necessary for the VP response to fear stimuli.     

Is the right amygdala involved in visuospatial memory? Evidence from MRI volumetric measures

Quantitative MRI measurement of hippocampal sclerosis in patients suffering from temporal lobe epilepsy (TLE) have, as yet, failed to evidence any correlation between the right hippocampus and visuospatial memory. In this report, word learning and design learning tasks were carried out as well as MRI volumetric measurements of the hippocampus and amygdala in order to verify possible modality-specific correlations between function and structure. Delayed recall indices in our memory tasks provided significant results. Visuoverbal ratios differed between right and left TLE groups, as did laterality indices of hippocampal and amygdalar volumes. Furthermore, correlations were found between the left hippocampal volume and verbal memory, and between the right amygdala and visuospatial memory. We suggest that the difficulty encountered in establishing a correlation between right temporal structures and visuospatial memory could come both from the type of test employed and the structures considered.     

Stress-induced activation of the dynorphin/κ-opioid receptor system in the amygdala potentiates nicotine conditioned place preference

Many smokers describe the anxiolytic and stress-reducing effects of nicotine, the primary addictive component of tobacco, as a principal motivation for continued drug use. Recent evidence suggests that activation of the stress circuits, including the dynorphin/κ-opioid receptor system, modulates the rewarding effects of addictive drugs. In the present study, we find that nicotine produced dose-dependent conditioned place preference (CPP) in mice. κ-receptor activation, either by repeated forced swim stress or U50,488 (5 or 10 mg/kg, i.p.) administration, significantly potentiated the magnitude of nicotine CPP. The increase in nicotine CPP was blocked by the κ-receptor antagonist norbinaltorphimine (norBNI) either systemically (10 mg/kg, i.p.) or by local injection in the amygdala (2.5 μg) without affecting nicotine reward in the absence of stress. U50,488 (5 mg/kg, i.p.) produced anxiety-like behaviors in the elevated-plus maze and novel object exploration assays, and the anxiety-like behaviors were attenuated both by systemic nicotine (0.5 mg/kg, s.c.) and local injection of norBNI into the amygdala. Local norBNI injection in the ventral posterior thalamic nucleus (an adjacent brain region) did not block the potentiation of nicotine CPP or the anxiogenic-like effects of κ-receptor activation. These results suggest that the rewarding effects of nicotine may include a reduction in the stress-induced anxiety responses caused by activation of the dynorphin/κ-opioid system. Together, these data implicate the amygdala as a key region modulating the appetitive properties of nicotine, and suggest that κ-opioid antagonists may be useful therapeutic tools to reduce stress-induced nicotine craving.     

The effects of the co-administration of the α₁-adrenoreceptor antagonist prazosin on the anxiolytic effect of citalopram in conditioned fear stress in the rat

Several studies have shown that the α₁-adrenoreceptor is involved in controlling extracellular serotonin levels. The administration of the α₁-adrenoreceptor antagonist prazosin was shown to decrease extracellular serotonin levels in the hippocampus, the prefrontal cortex and the raphe nucleus, while the administration of the α₁-adrenoreceptor agonist cirazoline was shown to increase serotonin levels. Furthermore, the elevation of serotonin levels induced by the selective serotonin reuptake inhibitor (SSRI) citalopram was attenuated by prazosin. Thus, α₁-adrenoreceptor antagonists may affect SSRI-induced increases in extracellular serotonin levels and their antidepressive and anxiolytic effects. However, little is known about the influence of α₁-adrenoreceptor antagonists on the behavioral pharmacological effects of SSRIs. The conditioned fear stress-induced freezing behavior is an animal model of anxiety and can detect the anxiolytic effect of SSRIs. To clarify whether an α₁-adrenoreceptor antagonist affects the anxiolytic action of SSRIs, we examined the effects of the co-administration of the α₁-adrenoreceptor antagonist prazosin and the SSRI citalopram using the contextual conditioned fear stress model. Low-dose prazosin (0.03 mg/kg) significantly attenuated the citalopram (3 mg/kg)-induced decrease in conditioned freezing. Moreover, high-dose (0.5 mg/kg), but not low-dose (0.03 mg/kg), prazosin significantly attenuated citalopram (10 mg/kg)-induced decreases in conditioned freezing. These drugs did not affect the spontaneous motor activity of the rats. Therefore, these results suggest that blocking the α₁-adrenoreceptor decreases the anxiolytic effect of citalopram.     

Co-localization of tau and α-synuclein in the olfactory bulb in Alzheimer’s disease with amygdala Lewy bodies

We recently reported that Alzheimer's disease (AD) with amygdala Lewy bodies (ALB) is a distinct form of alpha-synucleinopathy that occurs in advanced AD. In AD/ALB the alpha-synuclein pathology correlated with tau pathology, but not amyloid plaques, and there was often co-localization of tau and alpha-synuclein in the same neuron. Given the anatomical connectivity of the anterior olfactory nucleus and the amygdala, which receives axonal projections from the olfactory bulb, we hypothesized that there might be a relationship between tau and alpha-synuclein pathology in the olfactory bulb and the amygdala in AD. We screened for alpha-synuclein pathology in the olfactory bulb in AD with and without ALB, and investigated its relationship with tau pathology. In 38 of 41 (93%) AD/ALB cases and 4 of 21 (19%) AD cases without ALB (AD/non-ALB), alpha-synuclein pathology was detected in the olfactory bulb. Double immunolabeling at the light and electron microscopic levels revealed co-localization of tau and alpha-synuclein in the olfactory bulb neurons and neurites. The severity of tau pathology correlated with alpha-synuclein pathology in the olfactory bulb. In addition, alpha-synuclein pathology in the olfactory bulb correlated with alpha-synuclein pathology in amygdala. Tau pathology was greater in both the olfactory bulb and amygdala in AD/ALB than in AD/non-ALB, but there was no difference in tau pathology between the two groups in other brain regions assessed. The present study shows that in AD/ALB, the olfactory bulb is nearly equally vulnerable to tau and alpha-synuclein pathology as the amygdala and suggests that neurodegeneration in these two anatomical regions is linked.     

Which is the best way for not feeling fear? Young children's strategies to regulate fear

Over the past decade several studies have demonstrated children's rich knowledge of emotions. In contrast, less is known about children's knowledge about strategies to regulate their own emotional states. While questionnaire data suggest a rather late development of strategies to regulate emotions, not beginning before middle childhood, theory-of-mind research suggests the possibility of an earlier development. The present study examines whether children from age three on are able to distinguish effective from ineffective strategies of emotion regulation. A total of 64 children (16 3-, 4,-5-, and 6-year-olds) were given six stories all depicting a child protagonist facing a fear-eliciting situation. For each story, two effective and two ineffective strategies were presented. The children's task was to judge whether the strategy would be helpful for not feeling scared. With the exception of the 3-year-olds, children of all age groups were better in understanding the mental strategies than the behavioral strategies. Thus, the results are in accordance with theory of mind research and indicate that recognizing effective behavioral and mental strategies begins to develop from three years onward.     

Can the fear recognition deficits associated with callous-unemotional traits be identified in early childhood?

Introduction: Callous-unemotional (CU) traits in the presence of conduct problems are associated with increased risk of severe antisocial behavior. Developmentally sensitive methods of assessing CU traits have recently been generated, but their construct validity in relation to neurocognitive underpinnings of CU has not been demonstrated. The current study sought to investigate whether the fear-specific emotion recognition deficits associated with CU traits in older individuals are developmentally expressed in young children as low concern for others and punishment insensitivity. Method: A subsample of 337 preschoolers (mean age 4.8 years, SD = 0.8) who completed neurocognitive tasks was taken from a larger project of preschool psychopathology. Children completed an emotional recognition task in which they were asked to identify the emotional face from the neutral faces in an array. CU traits were assessed using the Low Concern (LC) and Punishment Insensitivity (PI) subscales of the Multidimensional Assessment Profile of Disruptive Behavior (MAP-DB), which were specifically designed to differentiate the normative misbehavior of early childhood from atypical patterns. Results: High LC, but not PI, scores were associated with a fear-specific deficit in emotion recognition. Girls were more accurate than boys in identifying emotional expressions but no significant interaction between LC or PI and sex was observed. Conclusions: Fear recognition deficits associated with CU traits in older individuals were observed in preschoolers with developmentally defined patterns of low concern for others. Confirming that the link between CU-related impairments in empathy and distinct neurocognitive deficits is present in very young children suggests that developmentally specified measurement can detect the substrates of these severe behavioral patterns beginning much earlier than prior work. Exploring the development of CU traits and disruptive behavior disorders at very early ages may provide insights critical to early intervention and prevention of severe antisocial behavior.     

Is the hippocampus necessary for contextual fear conditioning?

The hippocampus is widely believed to be essential for learning about the context in which conditioning occurs. This view is based primarily on evidence that lesions of the dorsal hippocampus disrupt freezing to contextual cues after fear conditioning. However, lesions that disrupt freezing produce no effect on fear-potentiated startle, a second measure of contextual fear. Moreover, hippocampal lesions also do not disrupt the contextual ‘blocking’ phenomenon, which provides an indirect measure of contextual fear. In these paradigms, at least, it appears that hippocampal lesions disrupt the expression of freezing, rather than contextual fear itself. This interpretation is supported by the finding that rats showing preserved contextual blocking after hippocampal lesions show deficits not only in contextual freezing, but also in unconditioned freezing. These findings are consistent with a growing body of data from other conditioning paradigms that contextual learning is spared after lesions of the dorsal hippocampus. Nonetheless, there remain some reports of impaired contextual fear conditioning after hippocampal lesions that cannot be attributed easily to a disruption of freezing. Thus, it is concluded that the hippocampus may be involved in contextual learning under certain – as yet, unspecified – circumstances, but is not critical for contextual learning in general.     

Do seizures cause neuronal damage in rat amygdala kindling?

Using unbiased stereology, we estimated total neuronal numbers in the lateral, basal and accessory basal nuclei of the amygdala and in the hilus of the dentate gyrus 6 months after the induction of amygdala kindling. In kindled rats, there was no decrease in the total number of neurons in the various amygdaloid regions or the hilus compared to sham-operated animals. Furthermore, there was no correlation between the total duration of afterdischarges or the number of electrical stimulations and the number of neurons. Our data indicate that when using unbiased stereological methods, total neuronal number in the amygdala or hilus are not reduced after few amygdala-induced seizures.     

Discrimination of striatopallidum and extended amygdala in the rat: a role for parvalbumin immunoreactive neurons?

Synaptic effects of parvalbumin-immunoreactive (-ir) interneurons (PVs) upon medium spiny neurons may be essential to neural processing in the striatum and, in effect, may serve as an additional feature distinguishing striatum from extended amygdala. The present immunohistochemical study in the rat was done to evaluate the distributions of PVs in the striatum and extended amygdala. Numerous PVs occupy all structures currently regarded as having a striatal composition, including the caudate-putamen, nucleus accumbens, and olfactory tubercle, as well as structures that receive outputs from these, including the globus pallidus, ventral pallidum, entopeduncular nucleus and substantia nigra reticulata. The morphologies of striatal PVs and their distribution were similar to what has been previously reported. In addition, we found that the density of larger neostriatal PVs with extensive and densely immunoreactive dendritic and local axonal arbors is greatest laterally, particularly in striatal districts with slight calbindin-ir, including the striatal patch compartment. In contrast to the situation in striatum, few PVs were observed in the central and medial divisions of the extended amygdala, including the bed nucleus of stria terminalis, interstitial nucleus of the posterior limb of the anterior commissure and central and medial nuclei of the amygdala, or in mesopontine, peribrachial and medullary structures that receive extended amygdala output. The paucity of PVs may be a characteristic feature distinguishing extended amygdala and its projection areas from striatopallidum, as well as the general character of neural processing that occurs in each.     

β3 integrin is dispensable for conditioned fear and Hebbian forms of plasticity in the hippocampus

Integrins play key roles in the developing and mature nervous system, from promoting neuronal process outgrowth to facilitating synaptic plasticity. Recently, in hippocampal pyramidal neurons, β3 integrin (ITGβ3) was shown to stabilise synaptic AMPA receptors (AMPARs) and to be required for homeostatic scaling of AMPARs elicited by chronic activity suppression. To probe the physiological function for ITGβ3-dependent processes in the brain, we examined whether the loss of ITGβ3 affected fear-related behaviours in mice. ITGβ3-knockout (KO) mice showed normal conditioned fear responses that were similar to those of control wild-type mice. However, anxiety-like behaviour appeared substantially compromised and could be reversed to control levels by lentivirus-mediated re-expression of ITGβ3 bilaterally in the ventral hippocampus. In hippocampal slices, the loss of ITGβ3 activity did not compromise Hebbian forms of plasticity - neither acute pharmacological disruption of ITGβ3 ligand interactions nor genetic deletion of ITGβ3 altered long-term potentiation (LTP) or long-term depression (LTD). Moreover, we did not detect any changes in short-term synaptic plasticity upon loss of ITGβ3 activity. In contrast, acutely disrupting ITGβ1-ligand interactions or genetic deletion of ITGβ1 selectively interfered with LTP stabilisation whereas LTD remained unaltered. These findings indicate a lack of requirement for ITGβ3 in the two robust forms of hippocampal long-term synaptic plasticity, LTP and LTD, and suggest differential roles for ITGβ1 and ITGβ3 in supporting hippocampal circuit functions.     

Impaired P50 suppression in fear extinction in obsessive–compulsive disorder

The processes of fear conditioning and extinction are thought to be related to the pathophysiology of anxiety disorders including obsessive–compulsive disorder (OCD). We have reported alterations of auditory P50 suppression in human fear conditioning and extinction in healthy control subjects (Kurayama et al., 2009). In the study, P50 suppression was impaired transiently in the course of fear acquisition and extinction. In this study, we investigated the changes of P50 suppression with OCD patients in the course of the same experimental paradigm. 39 patients with OCD and 21 healthy control subjects were recruited. In the acquisition phase of classical fear conditioning, 10 pairings of the conditioned stimulus (CS; the visual stimulus from a light-emitting diode) and the unconditioned stimulus (US; the electrical stimulus to the wrist) were administered, and in the extinction phase, 10 CS without US were administered. P50 auditory evoked potentials were measured as the first stimulus sound (S1) and the second stimulus sound (S2) in double-click paradigm with a 500 ms interval. P50 S2/S1 ratio was used to evaluate P50 suppression. The mean P50 S2/S1 ratio in patients with OCD significantly elevated from baseline level during the fear acquisition as that in healthy controls, but the elevated S2/S1 ratio did not recover to baseline level. The S2/S1 ratio in the extinction phase was significantly higher in the OCD patient group than in the healthy control group. In conclusion, our data suggested that P50 sensory gating in fear extinction was impaired in patients with OCD.     

Tonic inhibition in principal cells of the amygdala: a central role for α3 subunit-containing GABAA receptors

GABAergic inhibition in the amygdala is essential in regulating fear and anxiety. Although fast "phasic" inhibition arising through the activation of postsynaptic GABA(A) receptors (GABA(A)Rs) has been well described in the amygdala, much less is known about extrasynaptic GABA(A)Rs mediating persistent or tonic inhibition and regulating neuronal excitability. Here, we recorded tonic currents in the basolateral (BLA) nucleus and the lateral (LA) nucleus of the amygdala. While all BLA principal cells expressed a robust GABAergic tonic current, only 70% of LA principal cells showed a tonic current. Immunohistochemical stainings revealed that the α3 GABA(A)R subunit is expressed moderately in the LA and strongly throughout the BLA nucleus, where it is located mostly at extrasynaptic sites. In α3 subunit KO mice, tonic currents are significantly reduced in BLA principal cells yet not in LA principal cells. Moreover, the α3 GABA(A)R-selective benzodiazepine site agonist and anxiolytic compound TP003 increases tonic currents and dampens excitability markedly in wild-type BLA principal cells but fails to do so in α3KO BLA cells. Interneurons of the LA and BLA nuclei also express a tonic current, but TP003-induced potentiation is seen in only a small fraction of these cells, suggesting that primarily other GABA(A)R variants underlie tonic inhibition in this cell type. Together, these studies demonstrate that α3 GABA(A)R-mediated tonic inhibition is a central component of the inhibitory force in the amygdala and that tonically activated α3 GABA(A)Rs present an important target for anxiolytic or fear-reducing compounds.     

Osmotic regulation of neuronal nitric oxide synthase expression in the rat amygdala: Functional role for nitric oxide in adaptive responses?

Water-deprivation-induced osmotic stress leads to activation of a number of adaptive responses. Nitric oxide (NO) has been implicated in the modulation of these responses, as the amygdala has been implicated in ingestive behavior and modulation of autonomic homeostatic functions. Here we investigated the effects of water deprivation on neuronal nitric oxide synthase (nNOS) expression within the rat amygdala; a brain area involved in modulating ingestive behavior and autonomic function. Water deprivation resulted in significant increases in nNOS immunoreactivity (-ir) within different regions of the amygdala compared with euhydrated rats. Maximal increases were observed in the anteroventral (118 +/- 9 vs. 47 +/- 3 neurons), anteriodorsal (133 +/- 9 vs. 77 +/- 3), and posterioventral (175 +/- 5 vs. 71 +/- 5) parts of the medial amygdala. The basomedial nucleus (65 +/- 4 vs. 39 +/- 3) and posterior basolateral nucleus (19 +/- 2 vs. 5 +/- 1) of the amygdala and the capsular (21 +/- 2 vs. 6 +/- 1) and medial (44 +/- 6 vs. 22 +/- 3) parts of the central nucleus of the amygdala also showed increased nNOS-ir in dehydrated rats. Water deprivation had no effect on nNOS-ir in areas such as the cortical, anterior basolateral, and intercalated nuclei of the amygdala. Microinjection of an NO donor, DEA-NONOate, into the central amygdala resulted in a pressor and tachycardic response that was attenuated by a soluble guanylate cyclase inhibitor. These observations suggest that activation of the nitrergic system is prevalent throughout the amygdala following water deprivation and suggest that the up-reguation of nNOS could play a significant role in the integrative response to osmotic stress.     

Phase-delay in the light–dark cycle impairs clock gene expression and levels of serotonin,norepinephrine, and their metabolites in the mouse hippocampus and amygdala

ObjectiveA number of animal studies have implicated circadian clock genes in the regulation of mood, anxiety, and reward. However, the effect of misalignment of the environmental light–dark and internal circadian clock on the monoamine system is not fully understood. In the present study, we examined whether an abnormal light–dark schedule would affect behavior-, circadian clock–, and monoamine-related gene expressions, along with monoamine contents in the amygdala and hippocampus of mice.MethodsMice were subjected to an 8-hour phase delay in the light–dark cycle (Shift) every two days for four weeks, and locomotor activity was continuously measured. We examined the circadian expression of clock genes (Per1, Per2, and Bmal1) and genes of the NE/5HT uptake transporters (Net and Sert). In addition, the levels of NE/5HT and their metabolites MHPG/5HIAA were analyzed in the amygdala and hippocampus.ResultsLocomotor activity showed a free-running phenotype with a longer period (>24 hours) and showed misalignment between the light–dark and inactive–active cycles. The amplitude of the day–night fluctuation of Bmal1 expression was reduced in the amygdala and hippocampus of light–dark–shifted mice. Net gene expression in the Shift group showed different profiles compared with the Control group. In addition, NE and 5HT levels in the amygdala of the Shift group increased during the active period.ConclusionsThe present results suggest that misalignment of the internal and external clocks by continuous shifting of the light–dark cycle affects the circadian clocks and monoamine metabolism in the amygdala and hippocampus of mice.     

Regulatable promoters and gene therapy for Parkinson's disease: is the only thing to fear, fear itself?

Gene therapy for Parkinson's disease has become a clinical reality with three different approaches currently being tested in patients. All three trials employ an adeno-associated virus with a type two serotype (AAV2). To date, no serious adverse events related to the injections of therapeutic vectors have been reported in any patient. This safety profile was predicted based upon, in some cases, exhaustive preclinical testing in both rodent and primate species. Still some argue that regulatable promoters are required so that expression of the transgene can be halted should untoward side effects arise. We argue that given the current empirical data base of AAV2, the lack of regulatable promoters that have been proven to be safe and effective, and the pressing clinical needs of PD patients, the mandatory use of regulatable vectors is not only unnecessary but, in some instances, misguided and potentially dangerous. This commentary will outline the issues related to the use of regulatable promoters for gene therapy for PD and express our opinion as to why mandating the use of such promoters might result in outcomes that are unsafe, unproductive, and counter to the progress of scientifically sound, clinical research.