Window into the songbird brain reveals superdiffusive migration of adult-born neurons.

In a recent study, Shvedov and colleagues used live two-photon imaging in transgenic zebra finches to reveal migration patterns of neuroblasts through the complex environment of the postembryonic brain. This study highlights the value of ubiquitin C/green fluorescent protein (UBC-GFP) transgenic zebra finches in studying adult neurogenesis and advances our understanding of dispersed long-distance neuronal migration in the adult brain, shedding light on this understudied phenomenon.

Differential effects of exposure to toxic or nontoxic mold spores on brain inflammation and Morris water maze performance.

People who live or work in moldy buildings often complain of "brain fog" that interferes with cognitive performance. Until recently, there was no published research on the effects of controlled exposure to mold stimuli on cognitive function or an obvious mechanism of action, fueling controversy over these claims. The constellation of health problems reported by mold-exposed individuals (respiratory issues, fatigue, pain, anxiety, depression, and cognitive deficits) correspond to those caused by innate immune activation following exposure to bacterial or viral stimuli. To determine if mold-induced innate immune activation might cause cognitive issues, we quantified the effects of both toxic and nontoxic mold on brain immune activation and spatial memory in the Morris water maze. We intranasally administered either 1) intact, toxic Stachybotrys chartarum spores; 2) ethanol-extracted, nontoxic Stachybotrys chartarum spores; or 3) control saline vehicle to mice. Inhalation of nontoxic spores caused significant deficits in the test of long-term memory of platform location, while not affecting short-term memory. Inhalation of toxic spores increased motivation to reach the platform. Interestingly, in both groups of mold-exposed males, numbers of interleukin-1ß-immunoreactive cells in many areas of the hippocampus significantly correlated with latency to find the platform, path length, and swimming speed during training, but not during testing for long-term memory. These data add to our prior evidence that mold inhalation can interfere with cognitive processing in different ways depending on the task, and that brain inflammation is significantly correlated with changes in behavior.

DARPP-32 distinguishes a subset of adult-born neurons in zebra finch HVC.

Adult male zebra finches (Taeniopygia guttata) continually incorporate adult-born neurons into HVC, a telencephalic brain region necessary for the production of learned song. These neurons express activity-dependent immediate early genes (e.g., zenk and c-fos) following song production, suggesting that these neurons are active during song production. Half of these adult-born HVC neurons (HVC NNs) can be backfilled from the robust nucleus of the arcopallium (RA) and are a part of the vocal motor pathway underlying learned song production, but the other half do not backfill from RA, and they remain to be characterized. Here, we used cell birth-dating, retrograde tract tracing, and immunofluorescence to demonstrate that half of all HVC NNs express the phosphoprotein DARPP-32, a protein associated with dopamine receptor expression. We also demonstrate that DARPP-32+ HVC NNs are contacted by tyrosine hydroxylase immunoreactive fibers, suggesting that they receive catecholaminergic input, have transiently larger nuclei than DARPP-32-neg HVC NNs, and do not backfill from RA. Taken together, these findings help characterize a group of HVC NNs that have no apparent projections to RA and so far have eluded positive identification other than HVC NN status.

Transection of the ventral hippocampal commissure impairs spatial reference but not contextual or spatial working memory.

Plasticity is a neural phenomenon in which experience induces long-lasting changes to neuronal circuits and is at the center of most neurobiological theories of learning and memory. However, too much plasticity is maladaptive and must be balanced with substrate stability. Area CA3 of the hippocampus provides such a balance via hemispheric lateralization, with the left hemisphere dominant in providing plasticity and the right specialized for stability. Left and right CA3 project bilaterally to CA1; however, it is not known whether this downstream merging of lateralized plasticity and stability is functional. We hypothesized that interhemispheric convergence of input from these pathways is essential for integrating spatial memory stored in the left CA3 with navigational working memory facilitated by the right CA3. To test this, we severed interhemispheric connections between the left and right hippocampi in mice and assessed learning and memory. Despite damage to this major hippocampal fiber tract, hippocampus-dependent navigational working memory and short- and long-term memory were both spared. However, tasks that required the integration of information retrieved from memory with ongoing navigational working memory and navigation were impaired. We propose that one function of interhemispheric communication in the mouse hippocampus is to integrate lateralized processing of plastic and stable circuits to facilitate memory-guided spatial navigation.

Unilateral vocal nerve resection alters neurogenesis in the avian song system in a region-specific manner.

New neurons born in the adult brain undergo a critical period soon after migration to their site of incorporation. During this time, the behavior of the animal may influence the survival or culling of these cells. In the songbird song system, earlier work suggested that adult-born neurons may be retained in the song motor pathway nucleus HVC with respect to motor progression toward a target song during juvenile song learning, seasonal song restructuring, and experimentally manipulated song variability. However, it is not known whether the quality of song per se, without progressive improvement, may also influence new neuron survival. To test this idea, we experimentally altered song acoustic structure by unilateral denervation of the syrinx, causing a poor quality song. We found no effect of aberrant song on numbers of new neurons in HVC, suggesting that song quality does not influence new neuron culling in this region. However, aberrant song resulted in the loss of left-side dominance in new neurons in the auditory region caudomedial nidopallium (NCM), and a bilateral decrease in new neurons in the basal ganglia nucleus Area X. Thus new neuron culling may be influenced by behavioral feedback in accordance with the function of new neurons within that region. We propose that studying the effects of singing behaviors on new neurons across multiple brain regions that differentially subserve singing may give rise to general rules underlying the regulation of new neuron survival across taxa and brain regions more broadly.

Mold inhalation causes innate immune activation, neural, cognitive and emotional dysfunction.

Individuals living or working in moldy buildings complain of a variety of health problems including pain, fatigue, increased anxiety, depression, and cognitive deficits. The ability of mold to cause such symptoms is controversial since no published research has examined the effects of controlled mold exposure on brain function or proposed a plausible mechanism of action. Patient symptoms following mold exposure are indistinguishable from those caused by innate immune activation following bacterial or viral exposure. We tested the hypothesis that repeated, quantified doses of both toxic and nontoxic mold stimuli would cause innate immune activation with concomitant neural effects and cognitive, emotional, and behavioral symptoms. We intranasally administered either 1) intact, toxic Stachybotrys spores; 2) extracted, nontoxic Stachybotrys spores; or 3) saline vehicle to mice. As predicted, intact spores increased interleukin-1ß immunoreactivity in the hippocampus. Both spore types decreased neurogenesis and caused striking contextual memory deficits in young mice, while decreasing pain thresholds and enhancing auditory-cued memory in older mice. Nontoxic spores also increased anxiety-like behavior. Levels of hippocampal immune activation correlated with decreased neurogenesis, contextual memory deficits, and/or enhanced auditory-cued fear memory. Innate-immune activation may explain how both toxic mold and nontoxic mold skeletal elements caused cognitive and emotional dysfunction.

Behavioral state-dependent lateralization of dorsal dentate gyrus c-Fos expression in mice.

Hemispheric lateralization is a fundamental organizing principle of nervous systems across taxonomic groups with bilateral symmetry. The mammalian hippocampus is lateralized anatomically, physiologically, and chemically; however, functional asymmetries are not yet well understood. Imaging studies in humans have implicated the left and right hippocampus in specialized processing. However, it is not clear if lateralized activity occurs in the rodent hippocampus. c-Fos imaging in animals provides a measure of neuronal activity with a resolution at the level of single cells. The aim of the present study was to determine whether lateralized activity-dependent c-Fos expression occurs in the rodent hippocampus. To understand functional lateralization of hippocampal processing, we compared interhemispheric expression of c-Fos in the dentate gyrus (DG), a structure involved in encoding new experiences, in mice that ran on a wheel, encoded a novel object, or remained in home cages. We found that wheel running (WR) induced the greatest amount of DG c-Fos expression in both hemispheres, with no difference between hemispheres. Object exploration (OB) resulted in left-lateralized DG c-Fos expression, whereas control (CON) mice were not lateralized. We then sought to determine whether differential consideration of hemispheres might influence the conclusions of a study by simulating common cell quantitation methods. We found that different approaches led to different conclusions. These data demonstrate lateralization of neuronal activity in the mouse DG corresponding to the experience of the animal and show that differentially considering hemisphere leads to alternative conclusions.

Adult Neurogenesis in the Songbird: Region-Specific Contributions of New Neurons to Behavioral Plasticity and Stability.

Our understanding of the role of new neurons in learning and encoding new information has been largely based on studies of new neurons in the mammalian dentate gyrus and olfactory bulb - brain regions that may be specialized for learning. Thus the role of new neurons in regions that serve other functions has yet to be fully explored. The song system provides a model for studying new neuron function in brain regions that contribute differently to song learning, song auditory discrimination, and song motor production. These regions subserve learning as well as long-term storage of previously learned information. This review examines the differences between learning-based and activity-based retention of new neurons and explores the potential contributions of new neurons to behavioral stability in the song motor production pathway.

Hemispheric asymmetry in new neurons in adulthood is associated with vocal learning and auditory memory.

Many brain regions exhibit lateral differences in structure and function, and also incorporate new neurons in adulthood, thought to function in learning and in the formation of new memories. However, the contribution of new neurons to hemispheric differences in processing is unknown. The present study combines cellular, behavioral, and physiological methods to address whether 1) new neuron incorporation differs between the brain hemispheres, and 2) the degree to which hemispheric lateralization of new neurons correlates with behavioral and physiological measures of learning and memory. The songbird provides a model system for assessing the contribution of new neurons to hemispheric specialization because songbird brain areas for vocal processing are functionally lateralized and receive a continuous influx of new neurons in adulthood. In adult male zebra finches, we quantified new neurons in the caudomedial nidopallium (NCM), a forebrain area involved in discrimination and memory for the complex vocalizations of individual conspecifics. We assessed song learning and recorded neural responses to song in NCM. We found significantly more new neurons labeled in left than in right NCM; moreover, the degree of asymmetry in new neuron numbers was correlated with the quality of song learning and strength of neuronal memory for recently heard songs. In birds with experimentally impaired song quality, the hemispheric difference in new neurons was diminished. These results suggest that new neurons may contribute to an allocation of function between the hemispheres that underlies the learning and processing of complex signals.

Adult neurogenesis is associated with the maintenance of a stereotyped, learned motor behavior.

Adult neurogenesis is thought to provide neural plasticity used in forming and storing new memories. Here we show a novel relationship between numbers of new neurons and the stability of a previously learned motor pattern. In the adult zebra finch, new projection neurons are added to the nucleus HVC and become part of the motor pathway for producing learned song. However, new song learning occurs only in juveniles and the behavioral impact of adding new neurons to HVC throughout life is unclear. We report that song changes after deafening are inversely correlated with the number of new neurons added to HVC, suggesting that adult neurogenesis in this context may contribute to behavioral stability. More broadly, we propose that new neuron function may depend on the site of integration and can vary as widely as promoting, or restricting, behavioral plasticity.

Using equivalence-based instruction to increase efficiency in teaching neuroanatomy.

A goal of all instruction is to efficiently allocate time spent teaching -- balancing redundancy that enhances learning with redundancy that is irrelevant to increasing student understanding. Efficient allocation of time allows the instructor to present additional material and go into more detail about the information being presented. Here we borrow laboratory research on concept formation and apply these formal principles in teaching introductory neuroanatomy within a lecture course on Behavioral Neuroscience. Concept formation is taught by pairing multiple stimuli, for instance brain name, location, and function, in such a way that novel associations within a category emerge without direct training. This study demonstrates that careful selection of associations by the instructor can encourage the spontaneous emergence of novel associations within a concept or category, thereby increasing efficiency of teaching and by extension, the depth of material that can be taught.

Alcohol dependence, disinhibited behavior and variation in the prodynorphin gene.

The results of the current analyses present preliminary evidence of an association between putatively functional variation in the prodynorphin (PDYN) gene and a dimensional measure of disinhibited behavior. A 68bp sequence in the core promoter region of the PDYN gene was genotyped in a community sample of 1021 adults aged 30-54. Participants were interviewed for lifetime history of DSM-IV alcohol dependence and completed two self-report measures of sensation seeking and impulsiveness. Fifteen percent (n=151) of the sample met DSM-IV criteria for alcohol dependence and while results did not support an association between the PDYN polymorphism and the diagnosis of alcohol dependence, we did observe an association between the "low" expressing L allele of the PDYN gene and a preference for engaging in disinhibited behavior. Additionally, people who had both a history of alcohol dependence and higher scores on this Disinhibited Behavior scale were most likely to carry an L allele. These results indicate that variation in the PDYN gene is associated with a dimensional trait or intermediate phenotype that reflects a preference for heavy drinking and engaging in related risky behaviors (e.g., drug use, sexual activity).

Ventromedial and medial preoptic hypothalamic ibotenic acid lesions potentiate systemic morphine analgesia in female, but not male rats.

Sex differences in systemic morphine analgesia occur with male rodents displaying significantly greater analgesic magnitudes and potencies than females. Neonatal androgenization, and to a lesser degree, adult ovariectomy enhance systemic morphine analgesia in female rats, implicating both organizational and activational effects of gonadal hormones. The neuroanatomical circuits sensitive to sex-related hormones by which females display a smaller opiate analgesic effect is not clear, but the ventromedial (VMH) and medial preoptic (MPOA) hypothalamic nuclei are critical in the monitoring of estradiol and other sex hormone levels. To assess the contribution of these nuclei to sex and adult gonadectomy differences in systemic morphine analgesia, intact male, intact female and adult ovariectomized (OVEX) female rats received bilateral saline (SAL) or ibotenic acid (IBO) microinjections into either the VMH or MPOA. Following surgeries, baseline tail-flick latencies over 120 minutes (min) were assessed over 4 days in all nine groups with intact females tested in the estrus phase of their cycle. All animals then received an ascending series of morphine (1.0, 2.5, 5.0, 7.5, 10.0mg/kg) injections 30min prior to the tail-flick test time course with 8-12 day inter-injection intervals between doses. Baseline latencies failed to differ between SAL-treated intact males and females, but were significantly higher in SAL-treated OVEX females. Both VMH IBO and MPOA IBO lesions increased baseline latencies in intact male and female rats, but not in OVEX females. SAL-treated intact males (ED(50)=4.0mg/kg) and SAL-treated OVEX females (ED(50)=3.5mg/kg) displayed significantly greater potencies of systemic morphine analgesia than SAL-treated intact females (ED(50)=6.3mg/kg), confirming previous gender and gonadectomy differences. Neither VMH IBO (ED(50)=3.7 mg/kg) nor MPOA IBO (ED(50)=4.1mg/kg) males differed from SAL-treated males in the potency of systemic morphine analgesia. In contrast, VMH IBO (ED(50)=4.1mg/kg) and MPOA IBO (ED(50)=3.5mg/kg) intact females displayed significantly greater potencies in systemic morphine analgesia than SAL-treated intact females. However, VMH IBO OVEX (ED(50)=3.5mg/kg) and MPOA IBO OVEX (ED(50)=3.9 mg/kg) failed to differ from SAL-treated OVEX females in the potency of systemic morphine analgesia. The magnitudes of systemic morphine analgesia as measured by Maximum Percentage Effect values displayed similar patterns, but lesser degrees, of effects. These data suggest that VMH and MPOA nuclei act to tonically inhibit endogenous pain-inhibitory circuits in the intact female, but not intact male brain, and that removal of circulating gonadal hormones by OVEX and/or excitotoxic destruction of these estrogen receptor accumulating nuclei disinhibit the female analgesic response to systemic morphine.

Deafening decreases neuronal incorporation in the zebra finch caudomedial nidopallium (NCM).

New neurons formed in the adult brain are incorporated into existing circuits. However, the number of new neurons recruited into a given brain region varies widely depending on the experience of the animal. An emerging general principle is that recruitment and early neuronal survival may be correlated with activity or use of the brain region. Here we show that use-dependent neuronal survival also occurs in the higher order auditory processing region of the songbird caudomedial nidopallium (NCM). We suggest that retention of young neurons may in part be influenced by use of the system without an increased demand for learning or behavioral plasticity.

Increasing stereotypy in adult zebra finch song correlates with a declining rate of adult neurogenesis.

Adult neurogenesis is often correlated with learning new tasks, suggesting that a function of incorporating new neurons is to permit new memory formation. However, in the zebra finch, neurons are added to the song motor pathway throughout life, long after the initial song motor pattern is acquired by about 3 months of age. To explore this paradox, we examined the relationship between adult song structure and neuron addition using sensitive measures of song acoustic structure. We report that between 4 and 15 months of age there was an increase in the stereotypy of fine-grained spectral and temporal features of syllable acoustic structure. These results indicate that the zebra finch continues to refine motor output, perhaps by practice, over a protracted period beyond the time when song is first learned. Over the same age range, there was a decrease in the addition of new neurons to HVC, a region necessary for song production, but not to Area X or the hippocampus, regions not essential for singing. We propose that age-related changes in the stereotypy of syllable acoustic structure and HVC neuron addition are functionally related.

Early auditory experience generates long-lasting memories that may subserve vocal learning in songbirds.

In both humans and songbirds, infants learn vocalizations by imitating the sounds of adult tutors with whom they interact during an early sensitive period. Vocal learning occurs in few animal taxa; similarities in the imitation process between humans and songbirds make the songbird a unique system in which vocal learning mechanisms can be studied at the neurobiological level. One theory of vocal learning proposes that early auditory experience generates auditory memories that subsequently guide vocal imitation. We now present a combination of behavioral and neurophysiological results, obtained in a songbird, that support this theory. We show that neurons in a forebrain auditory area of adult male zebra finches are selectively tuned to the song of a tutor heard early in development. Furthermore, the strength of this selectivity shows a striking correlation with the fidelity of vocal imitation, suggesting that this auditory memory may have served as the model for song learning.

Ultrasonic singing by the blue-throated hummingbird: a comparison between production and perception.

Blue-throated hummingbirds produce elaborate songs extending into the ultrasonic frequency range, up to 30 kHz. Ultrasonic song elements include harmonics and extensions of audible notes, non-harmonic components of audible syllables, and sounds produced at frequencies above 20 kHz without corresponding hearing range sound. To determine whether ultrasonic song elements function in intraspecific communication, we tested the hearing range of male and female blue-throated hummingbirds. We measured auditory thresholds for tone pips ranging from 1 kHz to 50 kHz using auditory brainstem responses. Neither male nor female blue-throated hummingbirds appear to be able to hear above 7 kHz. No auditory brainstem responses could be detected between 8 and 50 kHz at 90 dB. This high-frequency cutoff is well within the range reported for other species of birds. These results suggest that high-frequency song elements are not used in intraspecific communication. We propose that the restricted hummingbird hearing range may exemplify a phylogenetic constraint.