[Challenges and choices: translational acupuncture research spectrum-a proposal].

For more than half a century，the modern bioresearch in acupuncture has made remarkable advancements, proving scientific basis underlying the traditional, intuitive treatment, as well as leading to some new discoveries with the potential to enhance the effectiveness of acupuncture as we know it. Meanwhile, the clinical researches have started to shift its paradigm from traditional individual observation to modern evidence-based medicine. However, there is little interaction between basic and clinic researches, which are like two separate worlds, not benefiting each other. Also the education and training of acupuncture are still traditional style, little combining with modern studies. To bridging the large gap, we need translational science involving in. In this article, with a critical reviews of the limitations of the traditional methods of acupuncture, the challenges faced by clinic practices and placebo-control studies, and the advantages and disadvantages of basic research, we propose a methodological paradigm of the translational research, Translational Acupuncture Research Spectrum, that meets the current situation of acupuncture researches, hoping to give insights into this field and to promote modern acupuncture to move towards a new stage.

[The significance of "A neuroanatomical basis for electroacupuncture to drive the vagal-adrenal axis" published in Nature for acupuncture research].

October 2021, Nature published an original research article entitled A neuroanatomical basis for electroacupuncture to drive the vagal-adrenal axis, which draws great attention and arouses extensive discussion in the acupuncture field. Based on previous findings, this study demonstrates that the abundant innervation of PROKR2-Cre neurons in deep fascia tissues mediates the anti-inflammatory effect induced by low-intensity electroacupuncture stimulation at "Zusanli"（ST36） or "Shousanli"(LI10) via the "vagal-adrenal axis". This study is one of milestones in the field of acupuncture basic research and represents a great achievement generated by multi-discipline integration of acupuncture and neuro-immunology. It reveals partial contributing factors involved in acupuncture's effect and the relative specificity of the neuroanatomical basis of acupoints in the context of immune modulation. This study is both very informative and instructive for the innovation and clinical translation of future acupuncture research. Acupuncture researchers are recommended to attach great importance to this study in terms of its research strategy,methods and findings.

[Dilemma and breakthrough of acupuncture-moxibustion department under the situation of rapid expansion of hospital].

Under the situation of the rapid expansion of hospital, the dilemma of acupuncture-moxibustion department, as well as the relevant solutions are explored. The main reasons for the shrinking situation of the service in acupuncture-moxibustion department include: the disease-based department division trends to divert many diseases suitably treated in acupuncture-moxibustion department; the environment pursuing economic benefits restricts the development of acupuncture-moxibustion therapy characterized by "simple and low-cost operation". There are three important approaches for breaking through the dilemma of acupuncture and moxibustion therapy. First, modifying the traditional service mode as waiting for patients in acupuncture-moxibustion department and promoting acupuncture and moxibustion technology to be adopted in other departments rather than limited only in acupuncture-moxibustion department. Second, increasing the charges of acupuncture and moxibustion technology rationally. Third, positioning accurately the role of acupuncture and moxibustion technology in health services based on its own characteristics and advantages and promoting it in community medical institutions. All of these solutions require the guidance of supporting policies.

Dissociable contributions of phasic dopamine activity to reward and prediction.

Sensory cues that precede reward acquire predictive (expected value) and incentive (drive reward-seeking action) properties. Mesolimbic dopamine neurons' responses to sensory cues correlate with both expected value and reward-seeking action. This has led to the proposal that phasic dopamine responses may be sufficient to inform value-based decisions, elicit actions, and/or induce motivational states; however, causal tests are incomplete. Here, we show that direct dopamine neuron stimulation, both calibrated to physiological and greater intensities, at the time of reward can be sufficient to induce and maintain reward seeking (reinforcing) although replacement of a cue with stimulation is insufficient to induce reward seeking or act as an informative cue. Stimulation of descending cortical inputs, one synapse upstream, are sufficient for reinforcement and cues to future reward. Thus, physiological activation of mesolimbic dopamine neurons can be sufficient for reinforcing properties of reward without being sufficient for the predictive and incentive properties of cues.

[Discussion on Acupuncture as adjunctive therapy for chronic stable angina: a randomized clinical trial published in JAMA Internal Medicine].

Professor LIANG Fan-rong's team from Chengdu University of TCM published Acupuncture as adjunctive therapy for chronic stable angina: a randomized clinical trial in JAMA Internal Medicine on July 29, 2019, which demonstrates that acupuncture as an adjunctive therapy is safety and effective for mild and moderate chronic stable angina. Sixteen experts at home and abroad conducted serious discussions on the research design, evaluation methods, principles and mechanisms, clinical significance and enlightenment of future acupuncture research, and provided practical suggestions for acupuncture and moxibustion to go global and gain international recognition.

[Internationalized background of developing modern acupuncture and moxibustion-on the reform of teaching material of Acupuncture and Moxibustion].

This paper analyzes the severe challenges posed by the localization process in the internationalization of Chinese acupuncture and moxibustion to Chinese traditional acupuncture and moxibustion, and the ways to deal with the challenges. It is believed that the lack of deep understanding of the challenges in the process of internationalization of acupuncture and moxibustion is mainly due to the lack of knowledge structure of acupuncture and moxibustion, and the innovation of acupuncture and moxibustion teaching materials is the basis of effectively adjusting the knowledge structure. The direction of the reform of acupuncture and moxibustion teaching materials should separate the modern version of acupuncture and moxibustion that conforms to the nature of science and teach it in parallel with the traditional version of acupuncture and moxibustion. The development of modern acupuncture and moxibustion in line with the nature of science is not only an urgent need to meet the challenges of western acupuncture and moxibustion, but also an internal requirement for the development of acupuncture and moxibustion itself.

Acupuncture modulates immunity in sepsis: Toward a science-based protocol.

Sepsis is a serious medical condition in which immune dysfunction plays a key role. Previous treatments focused on chemotherapy to control immune function; however, a recognized effective compound or treatment has yet to be developed. Recent advances indicate that a neuromodulation approach with nerve stimulation allows developing a therapeutic strategy to control inflammation and improve organ functions in sepsis. As a quick, non-invasive technique of peripheral nerve stimulation, acupuncture has emerged as a promising therapy to provide significant advantages for immunomodulation in acute inflammation. Acupuncture obtains its regulatory effect by activating the somatic-autonomic-immune reflexes, including the somatic-sympathetic-splenic reflex, the somatic-sympathetic-adrenal reflex, the somatic-vagal-splenic reflex and the somatic-vagal-adrenal reflex, which produces a systemic effect. The peripheral nerve stimulation also induces local reflexes such as the somatic-sympathetic-lung-reflex, which then produces local effects. These mechanisms offer scientific guidance to design acupuncture protocols for immunomodulation and inflammation control, leading to an evidence-based comprehensive therapy recommendation.

[Bidirectional regulation of acupuncture and its plausible mechanisms].

The effects of acupuncture on functional regulation of biological systems have been studied extensively. The most interesting feature of acupuncture is the bidirectional regulatory ability to restore homeostatic values of body systems from either up or down states, which was found by Chinese biomedical researchers several decades ago, and has recently been observed by peers internationally. Acupuncture can produce two physiological response patterns, an immediate short-term response or/and a long-lasting response. The bidirectional regulatory effects of acupuncture are rarely observed under physiological states (normal homeostasis), rather, they are usually observed under pathological states (abnormal homeostasis) with long-lasting response patterns. This suggests that the effects of acupuncture under pathological states are different from the mechanisms under normal physiological states. This is important for understan-ding and developing acupuncture therapy, and also gives insight into understanding the biological control process itself. The present paper reviews the experimental literature and discusses the four conditions that produce bidirectional regulation of acupuncture, i.e. the inherent properties of the target systems, the functional states of the target system, the acupoint characteristics, and the stimulation parameters. Finally, two hypotheses are proposed to explain the mechanisms of bidirectional effects of acupuncture. The possible peripheral mechanism is that acupuncture can stimulate different types of peripheral nerve fibers to produce opposite regulatory effects; and the possible central mechanisms is that acupuncture might activate the adaptive control process of the central nervous system to restore homeostatic balance.

A Specific Component of the Evoked Potential Mirrors Phasic Dopamine Neuron Activity during Conditioning.

Midbrain dopamine (DA) neurons are thought to be a critical node in the circuitry that mediates reward learning. DA neurons receive diverse inputs from regions distributed throughout the neuraxis from frontal neocortex to the mesencephalon. While a great deal is known about changes in the activity of individual DA neurons during learning, much less is known about the functional changes in the microcircuits in which DA neurons are embedded. Here we used local field potentials recorded from the midbrain of behaving mice to show that the midbrain evoked potential (mEP) faithfully reflects the temporal and spatial structure of the phasic response of midbrain neuron populations during conditioning. By comparing the mEP to simultaneously recorded single units, we identified specific components of the mEP that corresponded to phasic DA and non-DA responses to salient stimuli. The DA component of the mEP emerged with the acquisition of a conditioned stimulus, was extinguished following changes in reinforcement contingency, and could be inhibited by pharmacological manipulations that attenuate the phasic responses of DA neurons. In contrast to single-unit recordings, the mEP permitted relatively dense sampling of the midbrain circuit during conditioning and thus could be used to reveal the spatiotemporal structure of multiple intermingled midbrain circuits. Finally, the mEP response was stable for months and thus provides a new approach to study long-term changes in the organization of ventral midbrain microcircuits during learning. Significance statement: Neurons that synthesize and release the neurotransmitter dopamine play a critical role in voluntary reward-seeking behavior. Much of our insight into the function of dopamine neurons comes from recordings of individual cells in behaving animals; however, it is notoriously difficult to record from dopamine neurons due to their sparsity and depth, as well as the presence of intermingled non-dopaminergic neurons. Here we show that much of the information that can be learned from recordings of individual dopamine and non-dopamine neurons is also revealed by changes in specific components of the local field potential. This technique provides an accessible measurement that could prove critical to our burgeoning understanding of the molecular, functional, and anatomical diversity of neuron populations in the midbrain.

The inhibitory microcircuit of the substantia nigra provides feedback gain control of the basal ganglia output.

Dysfunction of the basal ganglia produces severe deficits in the timing, initiation, and vigor of movement. These diverse impairments suggest a control system gone awry. In engineered systems, feedback is critical for control. By contrast, models of the basal ganglia highlight feedforward circuitry and ignore intrinsic feedback circuits. In this study, we show that feedback via axon collaterals of substantia nigra projection neurons control the gain of the basal ganglia output. Through a combination of physiology, optogenetics, anatomy, and circuit mapping, we elaborate a general circuit mechanism for gain control in a microcircuit lacking interneurons. Our data suggest that diverse tonic firing rates, weak unitary connections and a spatially diffuse collateral circuit with distinct topography and kinetics from feedforward input is sufficient to implement divisive feedback inhibition. The importance of feedback for engineered systems implies that the intranigral microcircuit, despite its absence from canonical models, could be essential to basal ganglia function. DOI: http://dx.doi.org/10.7554/eLife.02397.001.

Neural signals of extinction in the inhibitory microcircuit of the ventral midbrain.

Midbrain dopaminergic (DA) neurons are thought to guide learning via phasic elevations of firing in response to reward predicting stimuli. The mechanism for these signals remains unclear. Using extracellular recording during associative learning, we found that inhibitory neurons in the ventral midbrain of mice responded to salient auditory stimuli with a burst of activity that occurred before the onset of the phasic response of DA neurons. This population of inhibitory neurons exhibited enhanced responses during extinction and was anticorrelated with the phasic response of simultaneously recorded DA neurons. Optogenetic stimulation revealed that this population was, in part, derived from inhibitory projection neurons of the substantia nigra that provide a robust monosynaptic inhibition of DA neurons. Thus, our results elaborate on the dynamic upstream circuits that shape the phasic activity of DA neurons and suggest that the inhibitory microcircuit of the midbrain is critical for new learning in extinction.

Tripartite mechanism of extinction suggested by dopamine neuron activity and temporal difference model.

Extinction of behavior enables adaptation to a changing world and is crucial for recovery from disorders such as phobias and drug addiction. However, the brain mechanisms underlying behavioral extinction remain poorly understood. Midbrain dopamine (DA) neurons appear to play a central role in most acquisition processes of appetitive conditioning. Here, we show that the responses of putative DA neurons to conditioned reward predicting cues also dynamically encode two classical features of extinction: decrement in amplitude of previously learned excitatory responses and rebound of responding on subsequent retesting (spontaneous recovery). Crucially, this encoding involves development of inhibitory responses in the DA neurons, reflecting new, extinction-specific learning in the brain. We explored the implications of this finding by adding such inhibitory inputs to a standard temporal difference model of DA cell activity. We found that combining extinction-triggered plasticity of these inputs with a time-dependent spontaneous decay of weights, equivalent to a forgetting process as described in classical behavioral extinction literature, enabled the model to simulate several classical features of extinction. A key requirement to achieving spontaneous recovery was differential rates of spontaneous decay for weights representing original conditioning and for subsequent extinction learning. A testable prediction of the model is thus that differential decay properties exist within the wider circuits regulating DA cell activity. These findings are consistent with the hypothesis that extinction processes at both cellular and behavioral levels involve a dynamic interaction between new (inhibitory) learning, forgetting, and unlearning.

Dopamine cells respond to predicted events during classical conditioning: evidence for eligibility traces in the reward-learning network.

Behavioral conditioning of cue-reward pairing results in a shift of midbrain dopamine (DA) cell activity from responding to the reward to responding to the predictive cue. However, the precise time course and mechanism underlying this shift remain unclear. Here, we report a combined single-unit recording and temporal difference (TD) modeling approach to this question. The data from recordings in conscious rats showed that DA cells retain responses to predicted reward after responses to conditioned cues have developed, at least early in training. This contrasts with previous TD models that predict a gradual stepwise shift in latency with responses to rewards lost before responses develop to the conditioned cue. By exploring the TD parameter space, we demonstrate that the persistent reward responses of DA cells during conditioning are only accurately replicated by a TD model with long-lasting eligibility traces (nonzero values for the parameter lambda) and low learning rate (alpha). These physiological constraints for TD parameters suggest that eligibility traces and low per-trial rates of plastic modification may be essential features of neural circuits for reward learning in the brain. Such properties enable rapid but stable initiation of learning when the number of stimulus-reward pairings is limited, conferring significant adaptive advantages in real-world environments.

Pedunculopontine tegmental nucleus controls conditioned responses of midbrain dopamine neurons in behaving rats.

Midbrain dopamine (DA) neurons respond to sensory cues that predict reward. We tested the hypothesis that projections from the pedunculopontine tegmental nucleus (PPTg) are involved in driving this DA cell activity. First, the activity of PPTg and DA neurons was compared in a cued-reward associative learning paradigm. The majority of PPTg neurons showed phasic responses to the onset of sensory cues, at significantly shorter latency than DA cells, consistent with a PPTg-to-DA transmission of information. However, unlike DA cells, PPTg responses were almost entirely independent of whether signals were associated with rewards. Second, DA neuron responses to the cues were recorded in free-moving rats during reversible inactivation of the PPTg by microinfusion of local anesthetic. The results showed clear suppression of conditioned sensory responses of DA neurons after PPTg inactivation that was not seen after saline infusion or in non-DA cells. We propose that the PPTg relays information about the precise timing of attended sensory events, which is integrated with information about reward context by DA neurons.

The supramammillary area: its organization, functions and relationship to the hippocampus.

The supramammillary area of the hypothalamus, although small in size, can have profound modulatory effects on the hippocampal formation and related temporal cortex. It can control hippocampal plasticity and also has recently been shown to contain cells that determine the frequency of hippocampal rhythmical slow activity (theta rhythm). We review here its organization and anatomical connections providing an atlas and a new nomenclature. We then review its functions particularly in relation to its links with the hippocampus. Much of its control of behaviour and its differential activation by specific classes of stimuli is consistent with a tight relationship with the hippocampus. However, its ascending connections involve not only caudal areas of the cortex with close links to the hippocampus but also reciprocal connections with more rostral areas such as the infralimbic and anterior cingulate cortices. These latter areas appear to be the most rostral part of a network that, via the medial septum, hippocampus and lateral septum, is topographically mapped into the hypothalamus. The supramammillary area is thus diffusely connected with areas that control emotion and cognition and receives more topographically specific return information from areas that control cognition while also receiving ascending information from brain stem areas involved in emotion. We suggest that it is a key part of a network that recursively transforms information to achieve integration of cognitive and emotional aspects of goal-directed behaviour.

The role of the medial supramammillary nucleus in the control of hippocampal theta activity and behaviour in rats.

The medial supramammillary nucleus (mSUM) controls the frequency of hippocampal theta activity, completely in anaethsetized rats and partially in free-moving rats. mSUM could therefore influence hippocampal contributions to cognition and emotion. Using chemical lesions of mSUM in rats, we tested whether mSUM is involved in controlling several hippocampal-dependent functions: (i) defensive behaviour (open field, fear conditioning); (ii) behavioural inhibition (fixed interval schedule, differential reinforcement of low rates schedule); and (iii) spatial learning (water maze). Theta frequency was measured in all these tasks. mSUM lesions produced a pattern of changes in motivated/emotional behaviours (hyperactivity in defensive and operant tasks) similar to the pattern produced by hippocampal lesions, but had no significant effect on spatial learning. mSUM lesion decreased theta frequency modestly (by approximately 0.4 Hz) in behaving rats if the amount of movement was unchanged. There was not always a parallel between changes in theta frequency and behaviour; behaviours changed despite unchanged theta in defensive tasks and learning changed little despite a lower frequency of theta in the water maze task. This suggests that mSUM function impacts on emotional behaviour more than cognition, and can modulate theta and behaviour independently.