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Evolutionarily, olfaction is one of the oldest senses and pivotal for an individual’s health and survival. The olfactory bulb (OB), as the first olfactory relay station in the brain, is known to heavily process sensory information. To adapt to an animal’s needs, OB activity can be influenced by many factors either from within (intrinsic neuromodulation) or outside (extrinsic neuromodulation) the OB which include neurotransmitters, neuromodulators, hormones, and neuropeptides. Extrinsic sources seem to be of special importance as the OB receives massive efferent input from numerous brain centers even outweighing the sensory input from the nose. Here, we review neuromodulatory processes in the rodent OB from such extrinsic sources. We will discuss extrinsic neuromodulation according to points of origin, receptors involved, affected circuits, and changes in behavior. In the end, we give a brief outlook on potential future directions in research on neuromodulation in the OB.

Basal forebrain modulation of central circuits is associated with active sensation, attention, and learning. While cholinergic modulations have been studied extensively the effect of non-cholinergic basal forebrain subpopulations on sensory processing remains largely unclear. Here, we directly compare optogenetic manipulation effects of two major basal forebrain subpopulations on principal neuron activity in an early sensory processing area, i.e. mitral/tufted cells (MTCs) in the olfactory bulb. In contrast to cholinergic projections, which consistently increased MTC firing, activation of GABAergic fibers from basal forebrain to the olfactory bulb leads to differential modulation effects: while spontaneous MTC activity is mainly inhibited, odor-evoked firing is predominantly enhanced. Moreover, sniff-triggered averages revealed an enhancement of maximal sniff evoked firing amplitude and an inhibition of firing rates outside the maximal sniff phase. These findings demonstrate that GABAergic neuromodulation affects MTC firing in a bimodal, sensory-input dependent way, suggesting that GABAergic basal forebrain modulation could be an important factor in attention mediated filtering of sensory information to the brain.

Cognitive function in healthy aging and neurodegenerative diseases like Alzheimer’s disease (AD) correlates to olfactory performance. Aging and disease progression both show marked olfactory deficits in humans and rodents. As a clear understanding of what causes olfactory deficits is still missing, research on this topic is paramount to diagnostics and early intervention therapy. A recent development of this research is focusing on GABAergic interneurons. Both aging and AD show a change in excitation/inhibition balance, indicating reduced inhibitory network functions. In the olfactory system, inhibition has an especially prominent role in processing information, as the olfactory bulb (OB), the first relay station of olfactory information in the brain, contains an unusually high number of inhibitory interneurons. This review summarizes the current knowledge on inhibitory interneurons at the level of the OB and the primary olfactory cortices to gain an overview of how these neurons might influence olfactory behavior. We also compare changes in interneuron composition in different olfactory brain areas between healthy aging and AD as the most common neurodegenerative disease. We find that pathophysiological changes in olfactory areas mirror findings from hippocampal and cortical regions that describe a marked cell loss for GABAergic interneurons in AD but not aging. Rather than differences in brain areas, differences in vulnerability were shown for different interneuron populations through all olfactory regions, with somatostatin-positive cells most strongly affected.

Myostatin is shown to directly promote osteoclast differentiation, and its inhibition improves arthritic bone loss in two mouse models. Myostatin (also known as growth and differentiation factor 8) is a secreted member of the transforming growth factor-β (TGF-β) family that is mainly expressed in skeletal muscle, which is also its primary target tissue. Deletion of the myostatin gene ( Mstn ) in mice leads to muscle hypertrophy, and animal studies support the concept that myostatin is a negative regulator of muscle growth and regeneration 1 , 2 , 3 , 4 , 5 . However, myostatin deficiency also increases bone formation, mainly through loading-associated effects on bone 6 , 7 , 8 , 9 , 10 , 11 . Here we report a previously unknown direct role for myostatin in osteoclastogenesis and in the progressive loss of articular bone in rheumatoid arthritis (RA). We demonstrate that myostatin is highly expressed in the synovial tissues of RA subjects and of human tumor necrosis factor (TNF)-α transgenic (hTNFtg) mice, a model for human RA 12 . Myostatin strongly accelerates receptor activator of nuclear factor κB ligand (RANKL)-mediated osteoclast formation in vitro through transcription factor SMAD2-dependent regulation of nuclear factor of activated T-cells (NFATC1). Myostatin deficiency or antibody-mediated inhibition leads to an amelioration of arthritis severity in hTNFtg mice, chiefly reflected by less bone destruction. Consistent with these effects in hTNFtg mice, the lack of myostatin leads to increased grip strength and less bone erosion in the K/BxN serum-induced arthritis model in mice. The results strongly suggest that myostatin is a potent therapeutic target for interfering with osteoclast formation and joint destruction in RA.

The gaseous signalling molecule nitric oxide (NO) is involved in various physiological processes including regulation of blood pressure, immunocytotoxicity and neurotransmission. In the mammalian olfactory bulb (OB), NO plays a role in the formation of olfactory memory evoked by pheromones as well as conventional odorants. While NO generated by the neuronal isoform of NO synthase (nNOS) regulates neurogenesis in the olfactory epithelium, NO has not been implicated in olfactory signal transduction. We now show the expression and function of the endothelial isoform of NO synthase (eNOS) in mature olfactory sensory neurons (OSNs) of adult mice. Using NO-sensitive micro electrodes, we show that stimulation liberates NO from isolated wild-type OSNs, but not from OSNs of eNOS deficient mice. Integrated electrophysiological recordings (electro-olfactograms or EOGs) from the olfactory epithelium of these mice show that NO plays a significant role in modulating adaptation. Evidence for the presence of eNOS in mature mammalian OSNs and its involvement in odorant adaptation implicates NO as an important new element involved in olfactory signal transduction. As a diffusible messenger, NO could also have additional functions related to cross adaptation, regeneration, and maintenance of MOE homeostasis.

Pseudorabies virus (PrV) strains such as PrV-Bartha and its marker protein-expressing variants have been used in numerous studies as retrograde trans-neuronal tracing tools, defining the synaptic organization of mammalian neuronal circuits. However, the possibilities for functional examination of virus-infected neurons are limited to electrophysiological approaches or bulk loading strategies using calcium-sensitive dyes. Herein we report the generation and functional characterization of three PrV-Bartha—derived recombinant virus mutants that express different fluorescent calcium indicator proteins (FCIPs). All three generated virus recombinants are able to infect murine trigeminal neurons and express the corresponding FCIP (GCaMP2, camgaroo-2, or inverse pericam). Functionality of these virally expressed constructs was verified by using confocal Ca-imaging technologies. These FCIP-expressing virus recombinants provide a new tool for the functional analysis of whole circuits of synaptically connected neurons in vitro and in vivo .

Basal forebrain modulation of central circuits is associated with active sensation, attention and learning. While cholinergic modulations have been studied extensively the effect of non-cholinergic basal forebrain subpopulations on sensory processing remains largely unclear. Here, we directly compare optogenetic manipulation effects of two major basal forebrain subpopulations on principal neuron activity in an early sensory processing area, i.e. mitral/tufted cells (MTCs) in the olfactory bulb. In contrast to cholinergic projections, which consistently increased MTC firing, activation of GABAergic fibers from basal forebrain to the olfactory bulb lead to differential modulation effects: while spontaneous MTC activity is mainly inhibited, odor evoked firing is predominantly enhanced. Moreover, sniff triggered averages revealed an enhancement of maximal sniff evoked firing amplitude and an inhibition of firing rates outside the maximal sniff phase. These findings demonstrate that GABAergic neuromodulation affects MTC firing in a bimodal, sensory-input dependent way, suggesting that GABAergic basal forebrain modulation could be an important factor in attention mediated filtering of sensory information to the brain.

Processing of sensory information is substantially modulated by centrifugal projections from higher cortical areas, yet their behavioral relevance and underlying neural mechanisms remain unclear in most cases. The anterior olfactory nucleus (AON) is part of the olfactory cortex and its extensive connections to lower and higher brain centers put it in a prime position to modulate early sensory information in the olfactory system. Here, we show that optogenetic activation of AON neurons in awake animals was not perceived as an odorant equivalent cue. However, AON activation during odorant presentation reliably suppressed odor responses. This AON mediated effect was fast and constant across odors and concentrations. Likewise, activation of glutamatergic AON projections to the olfactory bulb (OB) transiently inhibited the excitability of mitral/tufted cells (MTCs) that relay olfactory input to cortex. Single-unit MTC recordings revealed that optogenetic activation of glutamatergic AON terminals in the OB transiently decreased sensory-evoked MTC spiking, regardless of the strength or polarity of the sensory response. These findings suggest that glutamatergic AON projections to the OB suppress early olfactory processing by inhibiting OB output neurons and that the AON can dynamically gate sensory throughput to the cortex. The anterior olfactory nucleus (AON) as an olfactory information processing area sends extensive projections to lower and higher brain centers but the behavioral consequences of its activation have been scarcely investigated. Using behavioral tests in combination with optogenetic manipulation we show that in contrast to what has been suggested previously, the AON does not seem to form odor percepts but instead suppresses odor responses across odorants and concentrations. Furthermore, this study shows that glutamatergic cortical projections to the olfactory bulb suppress olfactory processing by inhibiting output neurons, pointing to a potential mechanisms by which the olfactory cortex can actively and dynamically gate sensory throughput to higher brain centers. AON stimulation suppresses odor responses across odorants and concentrations AON activation is not perceived as an odorant equivalent cue The AON dynamically shapes olfactory bulb output on a fast timescale AON input to the olfactory bulb strongly suppresses mitral/tufted cells firing