Stephen D. Shea

Representation of Natural Stimuli in the Rodent Main Olfactory Bulb

Natural odorants are complex mixtures of diverse chemical compounds. Monomolecular odorants are represented in the main olfactory bulb by distinct spatial patterns of activated glomeruli. However, it remains unclear how individual compounds contribute to population representations of natural stimuli, which appear to be unexpectedly sparse. We combined gas chromatography and intrinsic signal imaging to visualize glomerular responses to natural stimuli and their fractionated components. While whole stimuli activated up to 20 visible glomeruli, each fractionated component activated only one or few glomeruli, and most glomeruli were activated by only one component. Thus, responses to complex mixtures reflected activation by multiple components, with each contributing only a small part of the overall representation. We conclude that the population response to a complex stimulus is largely the sum of the responses to its individual components, and activation of an individual glomerulus independently signals the presence of a specific component.

Noradrenergic Induction of Odor-Specific Neural Habituation and Olfactory Memories

For many mammals, individual recognition of conspecifics relies on olfactory cues. Certain individual recognition memories are thought to be stored when conspecific odor cues coincide with surges of noradrenaline (NA) triggered by intensely arousing social events. Such familiar stimuli elicit reduced behavioral responses, a change likely related to NA-dependent plasticity in the olfactory bulb (OB). In addition to its role in these ethological memories, NA signaling in the OB appears to be relevant for the discrimination of more arbitrary odorants as well. Nonetheless, no NA-gated mechanism of long-term plasticity in the OB has ever been directly observed in vivo. Here, we report that NA release from locus ceruleus (LC), when coupled to odor presentation, acts locally in the main OB to cause a specific long-lasting suppression of responses to paired odors. These effects were observed for both food odors and urine, an important social recognition cue. Moreover, in subsequent behavioral tests, mice exhibited habituation to paired urine stimuli, suggesting that this LC-mediated olfactory neural plasticity, induced under anesthesia, can store an individual recognition memory that is observable after recovery.

Sexually divergent expression of active and passive conditioned fear responses in rats

Traditional rodent models of Pavlovian fear conditioning assess the strength of learning by quantifying freezing responses. However, sole reliance on this measure includes the de facto assumption that any locomotor activity reflects an absence of fear. Consequently, alternative expressions of associative learning are rarely considered. Here we identify a novel, active fear response (‘darting’) that occurs primarily in female rats. In females, darting exhibits the characteristics of a learned fear behavior, appearing during the CS period as conditioning proceeds and disappearing from the CS period during extinction. This finding motivates a reinterpretation of rodent fear conditioning studies, particularly in females, and it suggests that conditioned fear behavior is more diverse than previously appreciated. Moreover, rats that darted during initial fear conditioning exhibited lower freezing during the second day of extinction testing, suggesting that females employ distinct and adaptive fear response strategies that improve long-term outcomes. DOI: http://dx.doi.org/10.7554/eLife.11352.001

Broadly tuned and respiration-independent inhibition in the olfactory bulb of awake mice

Olfactory representations are shaped by brain state and respiration. The interaction and circuit substrates of these influences are unclear. Granule cells (GCs) in the main olfactory bulb (MOB) are presumed to sculpt activity reaching the cortex via inhibition of mitral/tufted cells (MTs). GCs potentially make ensemble activity more sparse by facilitating lateral inhibition among MTs and/or enforce temporally precise activity locked to breathing. Yet the selectivity and temporal structure of wakeful GC activity are unknown. We recorded GCs in the MOB of anesthetized and awake mice and identified state-dependent features of odor coding and temporal patterning. Under anesthesia, GCs were sparsely active and strongly and synchronously coupled to respiration. Upon waking, GCs desynchronized, broadened their tuning and largely fired independently from respiration. Thus, during wakefulness, GCs exhibited stronger odor responses with less temporal structure. We propose that during wakefulness GCs may shape MT odor responses through broadened lateral interactions rather than respiratory synchronization.

PTP1B inhibition suggests a therapeutic strategy for Rett syndrome

The X-linked neurological disorder Rett syndrome (RTT) presents with autistic features and is caused primarily by mutations in a transcriptional regulator, methyl CpG-binding protein 2 (MECP2). Current treatment options for RTT are limited to alleviating some neurological symptoms; hence, more effective therapeutic strategies are needed. We identified the protein tyrosine phosphatase PTP1B as a therapeutic candidate for treatment of RTT. We demonstrated that the PTPN1 gene, which encodes PTP1B, was a target of MECP2 and that disruption of MECP2 function was associated with increased levels of PTP1B in RTT models. Pharmacological inhibition of PTP1B ameliorated the effects of MECP2 disruption in mouse models of RTT, including improved survival in young male (Mecp2-/y) mice and improved behavior in female heterozygous (Mecp2-/+) mice. We demonstrated that PTP1B was a negative regulator of tyrosine phosphorylation of the tyrosine kinase TRKB, the receptor for brain-derived neurotrophic factor (BDNF). Therefore, the elevated PTP1B that accompanies disruption of MECP2 function in RTT represents a barrier to BDNF signaling. Inhibition of PTP1B led to increased tyrosine phosphorylation of TRKB in the brain, which would augment BDNF signaling. This study presents PTP1B as a mechanism-based therapeutic target for RTT, validating a unique strategy for treating the disease by modifying signal transduction pathways with small-molecule drugs.

Functional anatomy of forebrain vocal control pathways in the budgerigar (Melopsittacus undulatus)

Budgerigars throughout life are capable of learning to produce many different sounds including those of human speech. Like humans, budgerigars use multiple craniomotor systems and coordinate both orosensory and auditory feedback in specialized forebrain nuclei. Although budgerigar auditory-vocal learning has a different evolutionary origin from that of human speech, both the human and budgerigar systems can control F0 and can alter the distribution of energy in spectral bands by adjusting the filter properties of the vocal tract. This allows budgerigars to produce an extremely diverse array of calls including many broadband and highly complex sounds.

Noradrenergic Plasticity of Olfactory Sensory Neuron Inputs to the Main Olfactory Bulb

Sensory responses are modulated by internal factors including attention, experience, and brain state. This is partly due to fluctuations in neuromodulatory input from regions such as the noradrenergic locus ceruleus (LC) in the brainstem. LC activity changes with arousal and modulates sensory processing, cognition, and memory. The main olfactory bulb (MOB) is richly targeted by LC fibers and noradrenaline profoundly influences MOB circuitry and odor-guided behavior. Noradrenaline-dependent plasticity affects the output of the MOB; however. it is unclear whether noradrenergic plasticity also affects the input to the MOB from olfactory sensory neurons (OSNs) in the glomerular layer. Noradrenergic terminals are found in the glomerular layer, but noradrenaline receptors do not seem to acutely modulate OSN terminals in vitro. We investigated whether noradrenaline induces plasticity at the glomerulus. We used wide-field optical imaging to measure changes in odor responses following electrical stimulation of LC in anesthetized mice. Surprisingly, odor-evoked intrinsic optical signals at the glomerulus were persistently weakened after LC activation. Calcium imaging selectively from OSNs confirmed that this effect was due to suppression of presynaptic input and was prevented by noradrenergic antagonists. Finally, suppression of responses to an odor did not require precise coincidence of the odor with LC activation. However, suppression was intensified by LC activation in the absence of odors. We conclude that noradrenaline release from LC has persistent effects on odor processing already at the first synapse of the main olfactory system. This mechanism could contribute to arousal-dependent memories.

Whole-Brain Mapping of Neuronal Activity in the Learned Helplessness Model of Depression

Some individuals are resilient, whereas others succumb to despair in repeated stressful situations. The neurobiological mechanisms underlying such divergent behavioral responses remain unclear. Here, we employed an automated method for mapping neuronal activity in search of signatures of stress responses in the entire mouse brain. We used serial two-photon tomography to detect expression of c-FosGFP – a marker of neuronal activation – in c-fosGFP transgenic mice subjected to the learned helplessness (LH) procedure, a widely used model of stress-induced depression-like phenotype in laboratory animals. We found that mice showing “helpless” behavior had an overall brain-wide reduction in the level of neuronal activation compared with mice showing “resilient” behavior, with the exception of a few brain areas, including the locus coeruleus, that were more activated in the helpless mice. In addition, the helpless mice showed a strong trend of having higher similarity in whole-brain activity profile among individuals, suggesting that helplessness is represented by a more stereotypic brain-wide activation pattern. This latter effect was confirmed in rats subjected to the LH procedure, using 2-deoxy-2[18F]fluoro-D-glucose positron emission tomography to assess neural activity. Our findings reveal distinct brain activity markings that correlate with adaptive and maladaptive behavioral responses to stress, and provide a framework for further studies investigating the contribution of specific brain regions to maladaptive stress responses.

Behavioral state-dependent reconfiguration of song-related network activity and cholinergic systems

The song system of oscine songbirds mediates multiple complex perceptive and productive behaviors. These discrete behaviors are modulated according to external variables such as social context, directed attention and other forms of experience. In addition, sleep has been implicated in song learning and song maintenance. Changes in behavioral state are associated with complex changes in auditory responsiveness and tonic/bursting properties of song system neurons. Cholinergic input, principally from the basal forebrain has been implicated in some of these state-dependent properties. Cholinergic modulation may affect numerous song system nuclei, with in vivo and in vitro studies indicating that a major target of cholinergic input is the forebrain nucleus HVC. Within HVC, a muscarinic cholinergic system has strong regulatory effects on most neurons, and may serve to couple and uncouple circuitry within HVC projecting along the premotor pathway with circuitry within HVC projecting along the cortico-basal ganglia pathway. These observations begin to describe how neuromodulatory regulation in the song system may contribute to learning phenomena.

Cytoarchitecture of Vocal Control Nuclei in Nestling Budgerigars: Relationships to Call Development

Changes in the cytoarchitecture of vocal control nuclei were investigated in nestling budgerigars (Melopsittacus undulatus) from hatching to fledging (five to six weeks) in relation to changes in vocalizations produced by nestlings during this period. The nuclei investigated were the hypoglossal nucleus, dorsomedial nucleus of the intercollicular midbrain, central nucleus of the archistriatum, central nucleus of the lateral neostriatum, oval nucleus of the hyperstriatum ventrale, medial division of the oval nucleus of the anterior neostriatum, and magnocellular nucleus of the lobus parolfactorius. These nuclei have been shown to form functional circuits in adults related to vocal learning. Consistent with previously reported results, we found that call development could be described in terms of five different phases based on changes in the duration and segmentation of single and multiple segment foodbegging calls and the appearance of the first socially learned contact calls around the time of fledging. We also found that call segment duration exhibited an inverted U-shaped developmental function during the nestling period, as has been found for total call duration. Cytoarchitectonic studies revealed striking changes in the cellular architecture of vocal control nuclei during the first four weeks posthatching. At hatching the hypoglossal nucleus exhibits adult-like cytoarchitecture, and the central nucleus of the archistriatum and the central nucleus of the lateral neostriatum are distinguishable from surrounding fields. By one week posthatch, the central nucleus of the archistriatum exhibits an adult-like appearance, while other telencephalic vocal control nuclei do not exhibit adult-like cytoarchitecture until three to four weeks posthatching. By two weeks posthatching, the dorsomedial nucleus of the intercollicular midbrain also exhibits adult-like cytoarchitecture. We observed substantial decreases in the thickness of ventricular proliferation zones during this period, with decreases in ventricular zones occurring at about the same point that nuclei at corresponding levels come to exhibit adult-like cytoarchitectonic features. Of interest is the fact that cytoarchitectural development occurs asynchronously in different brain regions, with the appearance of adult-like characteristics in the hindbrain and midbrain occurring before the appearance of adult-like cytoarchitectonic characteristics in telencephalic nuclei. These results are consistent with recent lesion studies indicating that neither auditory feedback nor telencephalic vocal control nuclei are necessary for the production of foodbegging and other nestling calls until three to four weeks posthatching.