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Olfactory dysfunction is an early pre-motor symptom of Parkinson’s disease (PD) but the neural mechanisms underlying this dysfunction remain largely unknown. Aggregation of α-synuclein is observed in the olfactory bulb (OB) during the early stages of PD, indicating a relationship between α-synuclein pathology and hyposmia. Here we investigate whether and how α-synuclein aggregates modulate neural activity in the OB at the single-cell and synaptic levels. We induced α-synuclein aggregation specifically in the OB via overexpression of double-mutant human α-synuclein by an adeno-associated viral (AAV) vector. We found that α-synuclein aggregation in the OB decreased the ability of mice to detect odors and to perceive attractive odors. The spontaneous activity and odor-evoked firing rates of single mitral/tufted cells (M/Ts) were increased by α-synuclein aggregates with the amplitude of odor-evoked high-gamma oscillations increased. Furthermore, the decreased activity in granule cells (GCs) and impaired inhibitory synaptic function were responsible for the observed hyperactivity of M/Ts induced by α-synuclein aggregates. These results provide direct evidences of the role of α-synuclein aggregates on PD-related olfactory dysfunction and reveal the neural circuit mechanisms by which olfaction is modulated by α-synuclein pathology.

Olfactory receptor gene choice is an intricate example of monogenic and monoallelic expression, where one out of over 1000 receptor genes is transcribed in each olfactory sensory neuron. This process involves expression of multiple olfactory receptor genes in immature neurons, followed by silencing of all but one receptor genes during maturation. However, the molecular identity of the repressors remains mysterious. Here, we discover TRIM66 as a key repressor. Multiple receptor genes are retained at low levels in most single mature OSNs after deletion of Trim66 , leading to decreased expression of the vast majority of olfactory receptor genes. Mechanistically, TRIM66 can bind to, assembly, and repress olfactory receptor enhancers, thereby silencing extra olfactory receptor genes. Functionally, deletion of Trim66 leads to severe defects in the olfactory information processing and innate olfactory behaviors. Our study provides the missing link in understanding the transition from polygenic to monogenic olfactory receptor expression. In our nose, each mature olfactory sensory neuron expresses only one out of 1,000 olfactory receptor genes. This study shows that an epigenetic repressor, TRIM66 ensures this rule by assembling olfactory enhancers and repressing their activity.

Norepinephrine (NE) released from locus coeruleus (LC) noradrenergic (NAergic) neurons plays a pivotal role in the regulation of olfactory behaviors. However, the precise circuits and receptor mechanisms underlying this function are not well understood. Here, in DBH-Cre mice model, we show that LC NAergic neurons project directly to both anterior piriform cortex (aPC) and the olfactory bulb (OB). By using pharmacological and optogenetic manipulations in vitro and in vivo, we found that NE reduces the excitability of aPC pyramidal neurons directly via α2 receptors and that it bidirectionally regulates the activity of OB mitral cells via modulation of inhibitory inputs. Activation of the NAergic projection reduced both spontaneous and odor-evoked activity in the aPC/OB in awake mice, enhanced the odor-decoding ability of the aPC, and decreased the odor-decoding ability of the OB. Furthermore, activation of LC–aPC/OB NAergic projections accelerated odor discrimination and specific inactivation of the LC–aPC/OB NAergic pathway impaired olfactory detection and discrimination. These findings identify the mechanism underlying NAergic modulation of the aPC/OB and elucidate its role in odor processing and olfactory behaviors. Norepinephrine play critical roles in regulating olfactory behaviors, but the precise circuits and mechanisms underlying this function remain unclear. Here, authors show how LC–aPC/OB NAergic pathway regulate odor processing and olfactory discrimination.

The olfactory system receives extensive serotonergic inputs from the dorsal raphe, a nucleus involved in control of behavior, regulation of mood, and modulation of sensory processing. Although many studies have investigated how serotonin modulates the olfactory bulb, few have focused on the anterior piriform cortex (aPC), a region important for olfactory learning and encoding of odor identity and intensity. Specifically, the mechanism and functional significance of serotonergic modulation of the aPC remain largely unknown. Here we used pharmacologic, optogenetic, and fiber photometry techniques to examine the serotonergic modulation of neural activity in the aPC in vitro and in vivo. We found that serotonin (5-HT) reduces the excitability of pyramidal neurons directly via 5-HT2C receptors, phospholipase C, and calcium-activated potassium (BK) channels. Furthermore, endogenous serotonin attenuates odor-evoked calcium responses in aPC pyramidal neurons. These findings identify the mechanism underlying serotonergic modulation of the aPC and shed light on its potential role.

Modulation of neural circuits is essential for flexible sensory perception and decision-making in a changing environment. Cholinergic and GABAergic projections to the olfactory system from the horizontal limb of the diagonal band of Broca (HDB) in the basal forebrain are crucial for odor detection and olfactory learning. Although studies have demonstrated that HDB neurons respond during olfactory learning, how cholinergic and GABAergic neurons differ in their response dynamics and roles in olfactory learning remains unclear. In this study, we examined the response profiles of these two subpopulations of neurons during passive odor exposure and associative olfactory learning. We show that the excitatory responses in both cholinergic and GABAergic neurons tended to habituate during repeated passive odor exposure. However, while these habituated responses were also observed in GABAergic neurons during a go-go task, there was no such habituation in cholinergic neurons. Moreover, the responses to S+ and S− trials diverged in cholinergic neurons once mice learned a go/no-go task. Furthermore, chemogenetic inactivation of cholinergic neurons in the HDB impaired odor discrimination. Together, these findings suggest that cholinergic neurons in the HDB reflect attention to positive reinforcement and may regulate odor discrimination via top–down inputs to the olfactory system.

In the olfactory bulb, olfactory information is translated into ensemble representations by mitral/tufted cells, and these representations change dynamically in a context-dependent manner. In particular, odor representations in mitral/tufted cells display pattern separation during odor discrimination learning. Although granule cells provide major inhibitory input to mitral/tufted cells and play an important role in pattern separation and olfactory learning, the dynamics of ensemble representation in granule cells during odor discrimination learning remain largely unknown. Here, we studied odor representation in granule cells of the olfactory bulb using fiber photometry recordings in awake behaving mice. We found that odors evoked reliable, excitatory responses in the granule cell population. Intriguingly, during odor discrimination learning, odor representation in granule cells exhibited improved separation and contained information about odor value. In conclusion, we show that granule cells in the olfactory bulb display learning-related plasticity, suggesting that they may mediate pattern separation in mitral/tufted cells.

Olfaction and satiety status influence each other: cues from the olfactory system modulate eating behavior, and satiety affects olfactory abilities. However, the neural mechanisms governing the interactions between olfaction and satiety are unknown. Here, we investigate how an animal’s nutritional state modulates neural activity and odor representation in the mitral/tufted cells of the olfactory bulb, a key olfactory center that plays important roles in odor processing and representation. At the single-cell level, we found that the spontaneous firing rate of mitral/tufted cells and the number of cells showing an excitatory response both increased when mice were in a fasted state. However, the neural discrimination of odors slightly decreased. Although ongoing baseline and odor-evoked beta oscillations in the local field potential in the olfactory bulb were unchanged with fasting, the amplitude of odor-evoked gamma oscillations significantly decreased in a fasted state. These neural changes in the olfactory bulb were independent of the sniffing pattern, since both sniffing frequency and mean inhalation duration did not change with fasting. These results provide new information toward understanding the neural circuit mechanisms by which olfaction is modulated by nutritional status.

Gelatin methacryloyl (GelMA) hydrogels is a widely used bioink because of its good biological properties and tunable physicochemical properties, which has been widely used in a variety of tissue engineering and tissue regeneration. However, pure GelMA is limited by the weak mechanical strength and the lack of continuous osteogenic induction environment, which is difficult to meet the needs of bone repair. Moreover, GelMA hydrogels are unable to respond to complex stimuli and therefore are unable to adapt to physiological and pathological microenvironments. This review focused on the functionalization strategies of GelMA hydrogel based bioinks for bone regeneration. The synthesis process of GelMA hydrogel was described in details, and various functional methods to meet the requirements of bone regeneration, including mechanical strength, porosity, vascularization, osteogenic differentiation, and immunoregulation for patient specific repair, etc. In addition, the response strategies of smart GelMA-based bioinks to external physical stimulation and internal pathological microenvironment stimulation, as well as the functionalization strategies of GelMA hydrogel to achieve both disease treatment and bone regeneration in the presence of various common diseases (such as inflammation, infection, tumor) are also briefly reviewed. Finally, we emphasized the current challenges and possible exploration directions of GelMA-based bioinks for bone regeneration. This paper summarized the strategies for functionalization of GelMA-based bioinks, including property enhancement, stimulus response and adaptation to specific pathological microenvironments. [Display omitted] •The functionalization strategy of GelMA based bioink for bone tissue engineering was summarized.•The response strategies of GelMA to external physical stimulation and internal pathological microenvironment.•Major challenges and exploration directions of GelMA for bone regeneration.

Radioactive aerosols harmful to humans are often produced in nuclear accidents, and their source term characteristics (total volume and particle size distribution) and dispersion patterns have important implications for accident response and hazard assessment. However, experimental studies of radioactive aerosols cannot be directly conducted in open space due to the hazardous nature of radioactive aerosols. In this study, silver was used instead of plutonium to study the aerosol source term under different specific internal energy inputs (SIEI) to simulate a low order explosion in an accident. Results show that aerosol release fraction (ARF) and respirable release fraction (RRF) of silver increase linearly with SIEI first, then varies in a range of 8% ~ 19%, with a turning point at SIEI of 1.4 MJ/kg. Analysis suggests an increase of difference between ARF and RRF with respect to SIEI. The size distribution of silver aerosol around 10 µm is influenced by SIEI significantly, which could be possibly attributed to the interactions between silver aerosol and ambient aerosol (solid HE products or rust). Comparison between the source term of silver and plutonium suggests that silver is a good surrogate of plutonium in studying aerosol for SIEI of MJ/kg level.

Osteoprotegerin (OPG) is one of the protective factors of bony tissue. However, the function of OPG in cartilage tissues remains elusive. The aim of this study is to explore the function of OPG in the postnatal maintenance and the occurring of osteoarthritis (OA) of temporomandibular joint (TMJ) in the rodent models. We found that OPG expressed in the hypertrophic layer of the condylar cartilage and upregulated in the hyperocclusion-induced-TMJ-trauma rat. In the absence of OPG, the cartilage degradation occurred prior to that in WT mice, and the 3-month-old OPG-Knockout (OPG-KO) condyle showed decreased chondrocyte proliferation and increased chondrocyte apoptosis, whereas the number of chondroclasts was comparable to WT condyle. The isolated chondrocytes from the OPG-KO mice also showed impaired survival and promoted chondrogenic differentiation. Furthermore, the hyperocclusion model deteriorated TMJ degradation in the OPG-KO mice. OPG plays a protective role in the condylar chondrocytes’ survival, and it is required for the postnatal maintenance of TMJ.