Christina Herold

Non-motor behavioural impairments in parkin-deficient mice.

Mutations in the parkin gene are the major cause of early‐onset familial Parkinsons disease (PD). We previously reported the generation and analysis of a knockout mouse carrying a deletion of exon 3 in the parkin gene. F1 hybrid pa+/– mice were backcrossed to wild‐type C57Bl/6 for three more generations to establish a pa–/–(F4) mouse line. The appearance of tyrosine hydroxylase‐positive neurons was normal in young and aged pa–/– (F4) animals. Loss of parkin function in mice did not enhance vulnerability of dopaminergic neurons to 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) toxicity. However, the pa–/– (F4) mice displayed impaired exploration and habituation to a new environment and exhibited thigmotaxis behaviour in the open field and Morris water maze. Abnormal anxiety‐related behaviour of pa–/– (F4) mice was also observed in the light/dark exploration test paradigm. Dopamine metabolism was enhanced in the striatum of pa–/– (F4) mice, as revealed by increased homovanillic acid (HVA) content and a reduced ratio of dihydroxyphenylacetic acid (DOPAC)/HVA. The alterations found in the dopaminergic system could be responsible for the behavioural impairments of pa–/– (F4) mice. Consistent with a recent observation of cognitive dysfunction in parkin‐linked patients with PD, our findings provide evidence of a physiological role of parkin in non‐motor behaviour, possibly representing a disease stage that precedes dopaminergic neuron loss.

Cingulate area 32 homologies in mouse, rat, macaque and human: Cytoarchitecture and receptor architecture

Homologizing between human and nonhuman area 32 has been impaired since Brodmann said he could not homologize with certainty human area 32 to a specific cortical domain in other species. Human area 32 has four divisions, however, and two can be structurally homologized to nonhuman species with cytoarchitecture and receptor architecture: pregenual (p32) and subgenual (s32) in human and macaque monkey and areas d32 and v32 in rat and mouse. Cytoarchitecture showed that areas d32/p32 have a dysgranular layer IV in all species and that areas v32/s32 have large and dense neurons in layer V, whereas a layer IV is not present in area v32. Areas v32/s32 have the largest neurons in layer Va. Features unique to humans include large layer IIIc pyramids in both divisions, sparse layer Vb in area p32, and elongated neurons in layer VI, with area s32 having the largest layer Va neurons. Receptor fingerprints of both subdivisions of area 32 differed between species in size and shape, although AMPA/GABAA and NMDA/GABAA ratios were comparable among humans, monkeys, and rats and were significantly lower than in mice. Layers I–III of primate and rodent area 32 subdivisions share more similarities in their receptor densities than layers IV–VI. Monkey and human subdivisions of area 32 are more similar to each other than to rat and mouse subdivisions. In combination with intracingulate connections, the location, cytoarchitecture, and ligand binding studies demonstrate critical homologies among the four species. J. Comp. Neurol. 521:4189–4204, 2013.

The receptor architecture of the pigeons’ nidopallium caudolaterale: an avian analogue to the mammalian prefrontal cortex

The avian nidopallium caudolaterale is a multimodal area in the caudal telencephalon that is apparently not homologous to the mammalian prefrontal cortex but serves comparable functions. Here we analyzed binding-site densities of glutamatergic AMPA, NMDA and kainate receptors, GABAergic GABAA, muscarinic M1, M2 and nicotinic (nACh) receptors, noradrenergic α1 and α2, serotonergic 5-HT1A and dopaminergic D1-like receptors using quantitative in vitro receptor autoradiography. We compared the receptor architecture of the pigeons’ nidopallial structures, in particular the NCL, with cortical areas Fr2 and Cg1 in rats and prefrontal area BA10 in humans. Our results confirmed that the relative ratios of multiple receptor densities across different nidopallial structures (their “receptor fingerprints”) were very similar in shape; however, the absolute binding densities (the “size” of the fingerprints) differed significantly. This finding enables a delineation of the avian NCL from surrounding structures and a further parcellation into a medial and a lateral part as revealed by differences in densities of nACh, M2, kainate, and 5-HT1A receptors. Comparisons of the NCL with the rat and human frontal structures showed differences in the receptor distribution, particularly of the glutamate receptors, but also revealed highly conserved features like the identical densities of GABAA, M2, nACh and D1-like receptors. Assuming a convergent evolution of avian and mammalian prefrontal areas, our results support the hypothesis that specific neurochemical traits provide the molecular background for higher order processes such as executive functions. The differences in glutamate receptor distributions may reflect species-specific adaptations.

Differential increase of extracellular dopamine and serotonin in the ‘prefrontal cortex’ and striatum of pigeons during working memory

Monoamines, such as dopamine (DA) and serotonin (5‐HT), play a central role in the modulation of cognitive processes at the forebrain level. Experimental and clinical studies based on dopaminergic pathology, depletion or medication indicate that DA, in particular, is involved in working memory (WM). However, it is unclear whether DA is indeed related to WM, whether its function is specific to the prefrontal cortex (PFC), and whether other modulators, such as 5‐HT, might have similar functions. Therefore, the aims of this study were threefold. First, we analysed whether increased prefrontal DA release is related to WM in general or only to its short‐term memory component. Second, we examined whether the DA release during cognitive tasks is specific to prefrontal areas or also occurs in the striatum. Third, we analysed whether prefrontal or striatal 5‐HT release accompanies working and short‐term memory. We approached these questions by using in vivo microdialysis to analyse the extracellular DA and 5‐HT release in the pigeons ‘PFC’ and striatum during matching‐to‐sample tasks with or without a delay. Here, we show that DA has no unitary function but is differentially released during working as well as short‐term memory in the pigeons ‘prefrontal’ cortex. Striatal DA shows an increased efflux only during WM that involves a delay component. WM is also accompanied by a ‘prefrontal’ but not a striatal release of 5‐HT, whose efflux pattern is thus partly different to that of DA. Our findings thus show a triple dissociation between transmitters, structures and tasks within the avian ‘prefronto’‐striatal system.

Distribution of neurotransmitter receptors and zinc in the pigeon (Columba livia) hippocampal formation: A basis for further comparison with the mammalian hippocampus.

The avian hippocampal formation (HF) and mammalian hippocampus share a similar functional role in spatial cognition, but the underlying neuronal mechanisms allowing the functional similarity are incompletely understood. To understand better the organization of the avian HF and its transmitter receptors, we analyzed binding site densities for glutamatergic AMPA, NMDA, and kainate receptors; GABAA receptors; muscarinic M1, M2 and nicotinic (nACh) acetylcholine receptors; noradrenergic α1 and α2 receptors; serotonergic 5‐HT1A receptors; dopaminergic D1/5 receptors by using quantitative in vitro receptor autoradiography. Additionally, we performed a modified Timm staining procedure to label zinc. The regionally different receptor densities mapped well onto seven HF subdivisions previously described. Several differences in receptor expression highlighted distinct HF subdivisions. Notable examples include 1) high GABAA and α1 receptor expression, which rendered distinctive ventral subdivisions; 2) high α2 receptor expression, which rendered distinctive a dorsomedial subdivision; 3) distinct kainate, α2, and muscarinic receptor densities that rendered distinctive the two dorsolateral subdivisions; and 4) a dorsomedial region characterized by high kainate receptor density. We further observed similarities in receptor binding densities between subdivisions of the avian and mammalian HF. Despite the similarities, we propose that 300 hundred million years of independent evolution has led to a mosaic of similarities and differences in the organization of the avian HF and mammalian hippocampus and that thinking about the avian HF in terms of the strict organization of the mammalian hippocampus is likely insufficient to understand the HF of birds. J. Comp. Neurol. 522:2553–2575, 2014.

The maturation of research into the avian hippocampal formation: Recent discoveries from one of the nature's foremost navigators

For more than 30 years, a growing number of researchers have been attracted to the challenge of understanding the neurobiological organization of the avian hippocampal formation (HF) and its relationship to the remarkable spatial cognitive abilities of birds. In this selective review, we highlight recent anatomical and developmental findings that reveal a HF design that defies any simple comparison to the mammalian hippocampus and leaves unanswered the seemingly enduring question of whether a dentate gyrus homologue is to be found in HF. From a functional perspective, we highlight the recent discoveries that implicate HF in the use of space for memory pattern segregation and continued interest in the role HF neurogenesis may play in supporting memory function and its relationship to memory decline in aging birds. We also summarize data that nurture a fundamental reinterpretation of the role of HF in spatial cognition by suggesting HF involvement in spatial perception antecedent to any memory formation. Given the disproportionate adaptive significance of space for birds, which has led to the evolution of their exceptional navigational and memory abilities, there is little doubt that the avian HF will continue to provide important and unexpected insights into the neural basis of spatial cognition.

Stimulation of dopamine D1 receptors in the avian fronto-striatal system adjusts daily cognitive fluctuations

Several studies have shown that the level of dopaminergic transmission and D1 receptor signaling is crucial for working memory (WM) in the prefrontal cortex (PFC) of mammals. Thus, hyper- or hypostimulation of prefrontal D1 receptors are pathophysiological findings often involved in cognitive and WM impairments. These observations can be mimicked by supranormal stimulation or inhibition with D1 receptor agonists or D1 antagonists, respectively. As a consequence, it is assumed that there is a normal range of dopamine function in prefrontal cortex that can be described as an inverted U-shaped relationship between dopamine transmission, i.e. D1 receptor stimulation, and intact WM. If this is true, short-term fluctuations of cognitive performance might be described as small-scale adjustments along the tip of the inverted U-curve and should depend on D1 receptor stimulation. We tested this hypothesis in pigeons performing a delayed-matching-to-sample task (DMTS), a classic paradigm to test WM. We applied the D1 agonist SKF81297 and the D1 antagonist SCH23390 into the nidopallium caudolaterale (NCL), the avian functional analogue of the PFC, and simultaneously in the medial striatum (MSt), by in vivo microdialysis while the animals performed the task. Animals showed daily fluctuations in WM performance. While the D1 agonist was able to improve or to decrease performance during low or strong performance periods, respectively, performance did not differ from control with the D1 antagonist. This study shows that D1 receptors seem to calibrate differentially prefronto-striatal functions based on individual low or high performance states.

Plasticity in D1-like receptor expression is associated with different components of cognitive processes.

Dopamine D1-like receptors consist of D1 (D1A) and D5 (D1B) receptors and play a key role in working memory. However, their possibly differential contribution to working memory is unclear. We combined a working memory training protocol with a stepwise increase of cognitive subcomponents and real-time RT-PCR analysis of dopamine receptor expression in pigeons to identify molecular changes that accompany training of isolated cognitive subfunctions. In birds, the D1-like receptor family is extended and consists of the D1A, D1B, and D1D receptors. Our data show that D1B receptor plasticity follows a training that includes active mental maintenance of information, whereas D1A and D1D receptor plasticity in addition accompanies learning of stimulus-response associations. Plasticity of D1-like receptors plays no role for processes like response selection and stimulus discrimination. None of the tasks altered D2 receptor expression. Our study shows that different cognitive components of working memory training have distinguishable effects on D1-like receptor expression.

NMDA and D2-like receptors modulate cognitive flexibility in a color discrimination reversal task in pigeons.

Reversal and extinction learning represent forms of cognitive flexibility that refer to the ability of an animal to alter behavior in response to unanticipated changes on environmental demands. A role for dopamine and glutamate in modulating this behavior has been implicated. Here, we determined the effects of intracerebroventricular injections in pigeons forebrain of the D2-like receptor agonist quinpirole, the D2-like receptor antagonist sulpiride and the N-methyl-d-aspartate receptor antagonist AP-5 on initial acquisition and reversal of a color discrimination task. On day one, pigeons had to learn to discriminate two color keys. On day two, pigeons first performed a retention test, which was followed by a reversal of the reward contingencies of the two color keys. None of the drugs altered performance in the initial acquisition of color discrimination or affected the retention of the learned color key. In contrast, all drugs impaired reversal learning by increasing trials and incorrect responses in the reversal session. Our data support the hypothesis that D2-like receptor mechanisms, like N-methyl-d-aspartate receptor modulations, are involved in cognitive flexibility and relearning processes, but not in initial learning of stimulus-reward association.

Serotonin 5-HT1A receptor binding sites in the brain of the pigeon (Columba livia)

Present knowledge about the serotonergic system in birdbrains is very limited, although the pigeon was used as an animal model in various studies focused on the behavioral effects of serotonergic transmission. In the mammalian brain the 5-HT(1A) receptor is the most widespread serotonin receptor type, and is involved in various functions. Less is known about the distribution of 5-HT(1A) receptors in the avian species. Therefore, we analyzed serotonin 5-HT(1A) receptor binding sites in the pigeon brain using quantitative in vitro receptor autoradiography with the selective radioligand [³H]-8-hydroxy-2-(di-n-propylamino)tetralin ([³H]-8-OH-DPAT). The receptor is differentially distributed throughout the pigeon brain. High levels of 5-HT(1A) receptors are found in the nucleus pretectalis (PT). Moderate densities were detected in the tectum, as well as in the telencephalic nidopallium and hyperpallium. Very low levels were found in the hippocampal formation, the amygdaloid complex, the basal ganglia, and several thalamic nuclei. Furthermore, local variations in 5-HT(1A) receptor densities support the concept of further subdivisions of the entopallium. The regional distribution patterns of 5-HT(1A) receptors mostly display a similar distribution as found in homologue brain structures of mammals.