Can we build a neuroecology of innovativeness similar to that pioneered by David Sherry for spatial memory?

David Sherry's pioneering work on the neuroecology of spatial memory has three characteristics that could inspire studies on other cognitive processes: it was grounded in a robust prior literature in psychology and neuroscience; it identified several natural history contexts in which repeated independent evolution of spatial memory differences had occurred in different clades; it involved a precise cognitive ability with a precise neural substrate. We discuss the application of these three principles to a more domain-general trait-innovation. We argue that targeting the caudolateral nidopallium and its connected areas, favoring problem-solving over reversal learning as an experimental assay, and focusing on situations that involve environmental change, such as urbanization and invasion, can help the study of innovation progress, like the field of spatial memory has since 1989.

Speed-accuracy trade-off, detour reaching and response to PHA in Carib grackles.

Performance on different cognitive tasks varies between individuals within species. Recent evidence suggests that, in some species, this variation reflects the existence of coherent cognitive strategies bringing together positive and negative relationships between tasks. For example, Carib grackles show a speed-accuracy trade-off, where individuals that are fast at solving novel problems make more errors at discrimination learning than individuals that are slow solvers. Pathogens are thought to play a major role in shaping variation in cognition, either because different cognitive strategies lead to differential exposure to pathogens, or because investment in cognitive abilities is costly, limiting the ability to invest in anti-pathogen responses. In both cases, immunocompetence is expected to co-vary with cognition. Here, using wild-caught Carib grackles, we tested whether performance on reversal learning and detour-reaching tasks is associated with the speed-accuracy trade-off found in a previous study. In parallel, we measured the response of individuals to a phytohemagglutinin (PHA) injection, an immunoecological technique that assesses general immunity. Performance on two problem-solving tasks and two learning tasks was characterized by a speed-accuracy trade-off, reversal learning and discrimination learning performance being better in individuals with slower problem-solving performance. Detour-reaching performance was independent from this trade-off. Finally, our results show that PHA response was higher in accurate but slow grackles, and higher in grackles with better detour-reaching performance. Investigating the emergence and maintenance of variation in cognition in a framework integrating variation in physiology and life history is likely a major step towards a better understanding of the evolution of cognition.

Sex-dependent effects of chromogranin B P413L allelic variant as disease modifier in amyotrophic lateral sclerosis.

Recent genetic studies yielded conflicting results regarding a role for the variant chromogranin B (CHGB)P413L allele as a disease modifier in ALS. Moreover, potential deleterious effects of the CHGBP413L variant in ALS pathology have not been investigated. Here we report that in transfected cultured cells, the variant CHGBL413 protein exhibited aberrant properties including mislocalization, failure to interact with mutant superoxide dismutase 1 (SOD1) and defective secretion. The CHGBL413 transgene in SOD1G37R mice precipitated disease onset and pathological changes related to misfolded SOD1 specifically in female mice. However, the CHGBL413 variant also slowed down disease progression in SOD1G37R mice, which is in line with a very slow disease progression that we report for a Swedish woman with ALS who is carrier of two mutant SOD1D90A alleles and two variant CHGBP413L and CHGBR458Q alleles. In contrast, overexpression of the common CHGBP413 allele in SOD1G37R mice did not affect disease onset but significantly accelerated disease progression and pathological changes. As in transgenic mice, the CHGBP413L allele conferred an earlier ALS disease onset in women of Japanese and French Canadian origins with less effect in men. Evidence is presented that the sex-dependent effects of CHGBL413 allelic variant in ALS may arise from enhanced neuronal expression of CHGB in females because of a sex-determining region Y element in the gene promoter. Thus, our results suggest that CHGB variants may act as modifiers of onset and progression in some ALS populations and especially in females because of higher expression levels compared to males.

Innovativeness and the effects of urbanization on risk-taking behaviors in wild Barbados birds.

The effects of urbanization on avian cognition remain poorly understood. Risk-taking behaviors like boldness, neophobia and flight distance are thought to affect opportunism and innovativeness, and should also vary with urbanization. Here, we investigate variation in risk-taking behaviors in the field in an avian assemblage of nine species that forage together in Barbados and for which innovation rate is known from previous work. We predicted that birds from highly urbanized areas would show more risk-taking behavior than conspecifics from less urbanized parts of the island and that the differences would be strongest in the most innovative of the species. Overall, we found that urban birds are bolder, less neophobic and have shorter flight distances than their less urbanized conspecifics. Additionally, we detected between-species differences in the effect of urbanization on flight distance, more innovative species showing smaller differences in flight distance between areas. Our results suggest that, within successful urban colonizers, species differences in innovativeness may affect the way species change their risk-taking behaviors in response to the urban environment.

Morphological and molecular sexing of the monochromatic Barbados bullfinch, Loxigilla barbadensis.

The bullfinch Loxigilla barbadensis is an endemic passerine on the Caribbean island of Barbados that has only recently been taxonomically split from the Lesser Antillean bullfinch L. noctis. The trait that most clearly distinguishes L. barbadensis from L. noctis is the absence in the male of sexually dimorphic coloration of the body and throat feathers, with L. barbadensis males and females sharing the same dull brown plumage. Here we report, in 64 individuals netted throughout the island, the results of a discriminant analysis on two (wing length and tail length) to four morphological traits showing very high (97%) concordance with sexing via PCR using blood samples. Females also show a paler lower mandible, a trait that yields an 80% concordance with PCR sexing. We found one L. barbadensis male that had a noctis-like reddish throat patch, supporting the idea that sexual dichromatism is the ancestral condition and that male Barbados bullfinches have evolved cryptic coloration that now makes the species monochromatic.

Problem-solving skills are predicted by technical innovations in the wild and brain size in passerines.

Behavioural innovations can provide key advantages for animals in the wild, especially when ecological conditions change rapidly and unexpectedly. Innovation rates can be compared across taxa by compiling field reports of novel behaviours. Large-scale analyses have shown that innovativeness reduces extinction risk, increases colonization success and is associated with increased brain size and pallial neuron numbers. However, appropriate laboratory measurements of innovativeness, necessary to conduct targeted experimental studies, have not been clearly established, despite decades of speculation on the most suitable assay. Here we implemented a battery of cognitive tasks on 203 birds of 15 passerine species and tested for relationships at the interspecific and intraspecific levels with ecological metrics of innovation and brain size. We found that species better at solving extractive foraging problems had higher technical innovation rates in the wild and larger brains. By contrast, performance on other cognitive tasks often subsumed under the term behavioural flexibility, namely, associative and reversal learning, as well as self-control, were not related to problem-solving, innovation in the wild or brain size. Our study yields robust support for problem-solving as an accurate experimental proxy of innovation and suggests that novel motor solutions are more important than self-control or learning of modified cues in generating technical innovations in the wild.

Abnormal regenerative responses and impaired axonal outgrowth after nerve crush in TDP-43 transgenic mouse models of amyotrophic lateral sclerosis.

Tar DNA binding protein 43 (TDP-43) mislocalization and aggregation is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia. Moreover, TDP-43 mRNA was found to be upregulated by ∼2.5-fold in the spinal cord of sporadic ALS subjects. Here we have examined the effects of nerve injury in new transgenic mouse models overexpressing by approximately threefold wild-type or mutant (G348C) TDP-43 species. Four weeks after axonal crush of sciatic nerve, TDP-43 transgenic mice remained paralyzed at the injured limb unlike control mice, which had regained most of their normal mobility. In contrast to normal mice, TDP-43 transgenic mice exhibited sustained elevation of TDP-43 cytoplasmic levels in motor neurons after nerve crush, and the relocalization of TDP-43 to the nucleus was delayed by several weeks. After crush, peripherin and ubiquitin levels remained also significantly elevated in TDP-43 transgenic mice compared with control mice. Analysis of the sciatic nerve at 11 d after nerve crush showed that the number of regenerating axons in the distal portion of the lesion was considerably reduced in TDP-43 transgenic mice, especially in TDP-43(G348C) mice, which exhibited a reduction of ∼40%. In addition, markers of neuroinflammation were detected at much higher levels in TDP-43 transgenic mice. These results suggest that a deregulation of TDP-43 expression in ALS is a phenomenon that can affect the regenerative responses to neuronal injury and regrowth potential of axons.

Songbird species that display more-complex vocal learning are better problem-solvers and have larger brains.

Complex vocal learning, a critical component of human spoken language, has been assumed to be associated with more-advanced cognitive abilities. Tests of this hypothesis between individuals within a species have been inconclusive and have not been done across species. In this work, we measured an array of cognitive skills-namely, problem-solving, associative and reversal learning, and self-control-across 214 individuals of 23 bird species, including 19 wild-caught songbird species, two domesticated songbird species, and two wild-caught vocal nonlearning species. We found that the greater the vocal learning abilities of a species, the better their problem-solving skills and the relatively larger their brains. These conclusions held when controlling for noncognitive variables and phylogeny. Our results support a hypothesis of shared genetic and cognitive mechanisms between vocal learning, problem-solving, and bigger brains in songbirds.

Wild-type human SOD1 overexpression does not accelerate motor neuron disease in mice expressing murine Sod1 G86R.

Approximately 10% of the cases of amyotrophic lateral sclerosis (ALS) are inherited, with the majority of identified linkages in the gene encoding Cu/Zn superoxide dismutase (SOD1). Recent studies showed that human wild-type SOD1 (SOD1(WT)) overexpression accelerated disease in mice expressing human SOD1 mutants linked to ALS. However, there is a controversy whether the exacerbation mechanism occurs through coaggregation of human SOD1(WT) with SOD1 mutants, stabilization by SOD1(WT) of toxic soluble SOD1 species, or conversion of SOD1(WT) into toxic species through oxidative damage. To further address whether the exacerbation of disease requires misfolding, modifications, and/or interaction of SOD1(WT) with pathogenic forms of SOD1 species, we have studied the effect of human SOD1(WT) overexpression in mice expressing the murine mutant Sod1(G86R). Surprisingly, unlike a previous report with SOD1(G85R) mice, SOD1(WT) overexpression did not affect the life span of Sod1(G86R) mice. Our analysis of spinal cord extracts revealed a lack of heterodimerization or aggregation between human SOD1(WT) and mouse Sod1(G86R) proteins. Moreover, there was no evidence of conversion of SOD1(WT) into misfolded or abnormal SOD1 isoforms based on immunoreactivity with monoclonal antibodies specific to misfolded forms of SOD1 mutants and on analysis of SOD1 isoforms after two-dimensional gel electrophoresis. We conclude that a direct interaction between wild type and mutant forms of SOD1 is required for exacerbation of ALS disease by SOD1(WT) protein.

Neurobiological and Ecological Correlates of Avian Innovation.

In the wild, particularly in rapidly changing conditions, being capable of solving new problems can increase an animal's chances of survival and reproduction. In the current context of widespread habitat destruction and increasing urbanization, innovativeness might be a crucial trait. In the past few decades, birds have proven to be a model taxon for the study of innovation, thanks to the abundant literature on avian innovation reports. Innovation databases in birds have been successfully employed to assess associations between innovativeness and other traits such as invasion success, life history, generalism, and brain encephalization. In order to more directly assess the causes of variation in innovation, a complementary approach consists in measuring innovativeness in wild-caught animals using problem-solving tasks that mimic innovations in the field. This method can allow for finer scale evaluation of ecological and neural correlates of innovation. Here, I review some of the most important findings on the correlates of innovation, with a particular focus on neural ones. I conclude by discussing avenues for future research, which I suggest should focus on neurobiology.

Ablation of proliferating microglia does not affect motor neuron degeneration in amyotrophic lateral sclerosis caused by mutant superoxide dismutase.

Microglial activation is a hallmark of all neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Here, a detailed characterization of the microglial cell population within the spinal cord of a mouse model of familial ALS was performed. Using flow cytometry, we detected three distinct microglial populations within the spinal cord of mice overexpressing mutant superoxide dismutase (SOD1): mature microglial cells (CD11b(+), CD45(low)), myeloid precursor cells (CD11b(+), CD45(int)), and macrophages (CD11b(+), CD45(high)). Characterization of cell proliferation within the CNS of SOD1(G93A) mice revealed that the expansion in microglial cell population is mainly attributable to the proliferation of myeloid precursor cells. To assess the contribution of proliferating microglia in motor neuron degeneration, we generated CD11b-TK(mut-30); SOD1(G93A) doubly transgenic mice that allow the elimination of proliferating microglia on administration of ganciclovir. Surprisingly, a 50% reduction in reactive microglia specifically in the lumbar spinal cord of CD11b-TK(mut-30); SOD1(G93A) doubly transgenic mice had no effect on motor neuron degeneration. This suggests that proliferating microglia-expressing mutant SOD1 are not central contributors of the neurodegenerative process in ALS caused by mutant SOD1.

Divergence in problem-solving skills is associated with differential expression of glutamate receptors in wild finches.

Problem solving and innovation are key components of intelligence. We compare wild-caught individuals from two species that are close relatives of Darwin's finches, the innovative Loxigilla barbadensis, and its most closely related species in Barbados, the conservative Tiaris bicolor. We found an all-or-none difference in the problem-solving capacity of the two species. Brain RNA sequencing analyses revealed interspecific differences in genes related to neuronal and synaptic plasticity in the intrapallial neural populations (mesopallium and nidopallium), especially in the nidopallium caudolaterale, a structure functionally analogous to the mammalian prefrontal cortex. At a finer scale, we discovered robust differences in glutamate receptor expression between the species. In particular, the GRIN2B/GRIN2A ratio, known to correlate with synaptic plasticity, was higher in the innovative L. barbadensis. These findings suggest that divergence in avian intelligence is associated with similar neuronal mechanisms to that of mammals, including humans.

De novo PacBio long-read and phased avian genome assemblies correct and add to reference genes generated with intermediate and short reads.

Reference-quality genomes are expected to provide a resource for studying gene structure, function, and evolution. However, often genes of interest are not completely or accurately assembled, leading to unknown errors in analyses or additional cloning efforts for the correct sequences. A promising solution is long-read sequencing. Here we tested PacBio-based long-read sequencing and diploid assembly for potential improvements to the Sanger-based intermediate-read zebra finch reference and Illumina-based short-read Anna's hummingbird reference, 2 vocal learning avian species widely studied in neuroscience and genomics. With DNA of the same individuals used to generate the reference genomes, we generated diploid assemblies with the FALCON-Unzip assembler, resulting in contigs with no gaps in the megabase range, representing 150-fold and 200-fold improvements over the current zebra finch and hummingbird references, respectively. These long-read and phased assemblies corrected and resolved what we discovered to be numerous misassemblies in the references, including missing sequences in gaps, erroneous sequences flanking gaps, base call errors in difficult-to-sequence regions, complex repeat structure errors, and allelic differences between the 2 haplotypes. These improvements were validated by single long-genome and transcriptome reads and resulted for the first time in completely resolved protein-coding genes widely studied in neuroscience and specialized in vocal learning species. These findings demonstrate the impact of long reads, sequencing of previously difficult-to-sequence regions, and phasing of haplotypes on generating the high-quality assemblies necessary for understanding gene structure, function, and evolution.

Feeding innovations in a nested phylogeny of Neotropical passerines.

Several studies on cognition, molecular phylogenetics and taxonomic diversity independently suggest that Darwin's finches are part of a larger clade of speciose, flexible birds, the family Thraupidae, a member of the New World nine-primaried oscine superfamily Emberizoidea. Here, we first present a new, previously unpublished, dataset of feeding innovations covering the Neotropical region and compare the stem clades of Darwin's finches to other neotropical clades at the levels of the subfamily, family and superfamily/order. Both in terms of raw frequency as well as rates corrected for research effort and phylogeny, the family Thraupidae and superfamily Emberizoidea show high levels of innovation, supporting the idea that adaptive radiations are favoured when the ancestral stem species were flexible. Second, we discuss examples of innovation and problem-solving in two opportunistic and tame Emberizoid species, the Barbados bullfinch Loxigilla barbadensis and the Carib grackle Quiscalus lugubris fortirostris in Barbados. We review studies on these two species and argue that a comparison of L. barbadensis with its closest, but very shy and conservative local relative, the black-faced grassquit Tiaris bicolor, might provide key insights into the evolutionary divergence of cognition.

Bajan Birds Pull Strings: Two Wild Antillean Species Enter the Select Club of String-Pullers.

String-pulling is one of the most popular tests in animal cognition because of its apparent complexity, and of its potential to be applied to very different taxa. In birds, the basic procedure involves a food reward, suspended from a perch by a string, which can be reached by a series of coordinated pulling actions with the beak and holding actions of the pulled lengths of string with the foot. The taxonomic distribution of species that pass the test includes several corvids, parrots and parids, but in other families, data are much spottier and the number of individuals per species that succeed is often low. To date, the association between string-pulling ability and other cognitive traits was never tested. It is generally assumed that string-pulling is a complex form of problem-solving, suggesting that performance on string-pulling and other problem-solving tasks should be correlated. Here, we show that individuals of two innovative species from Barbados, the bullfinch Loxigilla barbadensis and the Carib grackle Quiscalus lugubris fortirostris, pass the string-pulling test. Eighteen of the 42 bullfinches tested succeeded, allowing us to correlate performance on this test to that on several other behavioral measurements. Surprisingly, string-pulling in bullfinches was unrelated to shyness, neophobia, problem-solving, discrimination and reversal learning performance. Only two of 31 grackles tested succeeded, precluding correlational analyses with other measures but still, the two successful birds largely differed in their other behavioral traits.

Convergent differential regulation of SLIT-ROBO axon guidance genes in the brains of vocal learners.

Only a few distantly related mammals and birds have the trait of complex vocal learning, which is the ability to imitate novel sounds. This ability is critical for speech acquisition and production in humans, and is attributed to specialized forebrain vocal control circuits that have several unique connections relative to adjacent brain circuits. As a result, it has been hypothesized that there could exist convergent changes in genes involved in neural connectivity of vocal learning circuits. In support of this hypothesis, expanding on our related study (Pfenning et al. [2014] Science 346: 1256846), here we show that the forebrain part of this circuit that makes a relatively rare direct connection to brainstem vocal motor neurons in independent lineages of vocal learning birds (songbird, parrot, and hummingbird) has specialized regulation of axon guidance genes from the SLIT-ROBO molecular pathway. The SLIT1 ligand was differentially downregulated in the motor song output nucleus that makes the direct projection, whereas its receptor ROBO1 was developmentally upregulated during critical periods for vocal learning. Vocal nonlearning bird species and male mice, which have much more limited vocal plasticity and associated circuits, did not show comparable specialized regulation of SLIT-ROBO genes in their nonvocal motor cortical regions. These findings are consistent with SLIT and ROBO gene dysfunctions associated with autism, dyslexia, and speech sound language disorders and suggest that convergent evolution of vocal learning was associated with convergent changes in the SLIT-ROBO axon guidance pathway.

Ablation of proliferating cells in the CNS exacerbates motor neuron disease caused by mutant superoxide dismutase.

Proliferation of glia and immune cells is a common pathological feature of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Here, to investigate the role of proliferating cells in motor neuron disease, SOD1(G93A) transgenic mice were treated intracerebroventicularly (i.c.v.) with the anti-mitotic drug cytosine arabinoside (Ara-C). I.c.v. delivery of Ara-C accelerated disease progression in SOD1(G93A) mouse model of ALS. Ara-C treatment caused substantial decreases in the number of microglia, NG2+ progenitors, Olig2+ cells and CD3+ T cells in the lumbar spinal cord of symptomatic SOD1(G93A) transgenic mice. Exacerbation of disease was also associated with significant alterations in the expression inflammatory molecules IL-1ß, IL-6, TGF-ß and the growth factor IGF-1.

Macrophage colony stimulating factor (M-CSF) exacerbates ALS disease in a mouse model through altered responses of microglia expressing mutant superoxide dismutase.

Macrophage colony stimulating factor (M-CSF) is a cytokine that regulates the survival, proliferation and maturation of microglial cells. Administration of M-CSF can promote neuronal survival in various models of central nervous system (CNS) injury. Here, in an attempt to induce a neuroprotective microglial cell phenotype and enhance motor neuron survival, mutant SOD1(G37R) transgenic mice were treated, weekly, with M-CSF starting at onset of disease. Unexpectedly, M-CSF accelerated disease progression in SOD1(G37R) mouse model of ALS. The shortened survival of M-CSF-treated animals was associated with diminished muscle innervation and enhanced adoption of a macrophage-like phenotype by microglial cells characterised by the upregulation of pro-inflammatory cytokines TNF-alpha and IL-1 beta and of the phagocytic marker CD68.