Journal of Neuroscience最新文献

(R,S)-Ketamine (ketamine) induces rapid and sustained antidepressant-relevant neuroplastogenic effects in vivo. The metabolite (2R,6R)-hydroxynorketamine (2R6R) forms shortly after the administration of ketamine and independently elicits rapid plasticity and sustained metaplasticity. Ketamine's therapeutic actions appear to result from distinct, time-sensitive plasticity phases, though the mechanisms that mediate these phases and whether these synaptic actions are unique to ketamine or 2R6R remain poorly understood. Here, we distinguished the synaptic actions of ketamine from its metabolites at the hippocampal Schaffer collateral→CA1 (SC→CA1) synapse. By modifying ketamine's chemical structure to hinder its metabolism to 2R6R or exposing slices to ketamine or 2R6R in vitro, we find that 2R6R, but not ketamine itself, induces rapid and sustained metaplasticity in both male and female mice. 2R6R's acute plasticity and sustained metaplasticity required mammalian target of rapamycin (mTOR)-dependent signaling, and both phases of 2R6R's synaptic effects were mimicked by pharmacological mTOR activation. Rapid, mTOR-dependent potentiation evoked by 2R6R was followed by long-lasting antidepressant-relevant behavior and metaplasticity that required activation of the inositol trisphosphate receptor. L-type Ca²⁺ channel signaling was required for only sustained synaptic actions, consistent with 2R6R's metaplasticity being activity-dependent. Pharmacological or antibody TrkB blockade after, but not before, 2R6R treatment prevented metaplastic synaptic priming, indicating a delayed contribution of BDNF/TrkB signaling. Blocking protein synthesis did not prevent 2R6R-induced metaplasticity. Our results implicate a sequence of plasticity mechanisms underlying 2R6R's synaptic actions in the hippocampus. These findings are relevant for the delineation of activity-dependent and time-sensitive synaptic mechanisms relevant to the treatment of neuropsychiatric disorders.

How does the brain adjust its decision processes to ensure timely decision completion? Computational modeling and electrophysiological investigations have pointed to dynamic "urgency" processes that serve to progressively reduce the quantity of evidence required to reach choice commitment as time elapses. In humans, such urgency dynamics have been observed exclusively in neural signals that accumulate evidence for a specific motor plan. Across three complementary experiments in humans (male and female), we characterize an electrophysiological signal that traces dynamic urgency and exhibits unique properties not observed in effector-selective signals. Firstly, it provides a representation of urgency alone, growing only as a function of time and not evidence strength. Secondly, when choice reports must be withheld until a response cue, this signal peaks and decays long before response execution, mirroring the early termination dynamics of a motor-independent evidence accumulation signal. These properties suggest that the brain may use urgency signals not only to expedite motor planning but also to hasten cognitive deliberation. These data demonstrate that urgency processes operate in a variety of perceptual choice scenarios and that they can be monitored in a model-independent manner via noninvasive brain signals.

The nucleus accumbens (NAc) is a critical node in the neural circuitry underlying reward and motivated behavior, including hedonic feeding, and its dysfunction is implicated in maladaptive behaviors in numerous psychiatric disorders. Medium spiny neurons (MSNs) in the NAc are predominantly categorized into dopamine 1 receptor-expressing (D1-MSNs) and dopamine 2 receptor-expressing (D2-MSNs) subtypes, which are thought to exert distinct and sometimes opposing roles in reward-related processes. Here, we used optogenetic, chemogenetic, and fiber photometry approaches in Cre driver mouse lines to dissect the causal contributions of D1- and D2-MSNs to the consumption of a high-fat diet (HFD) in sated animals. Activation of D1-MSNs via optogenetics or DREADDs significantly suppressed high-fat intake, whereas inhibition of these neurons increased consumption only in male but not female mice. Conversely, activation of D2-MSNs enhanced high-fat intake only in females, while their inhibition reduced intake in both sexes. Fiber photometry revealed dynamic shifts in D2-MSN activity over repeated high-fat exposures, with increasing activity correlating with escalating intake of HFD only in female mice. These results highlight opposing contributions of D1- and D2-MSN populations in regulating hedonic feeding and support a model in which salience and consumption are modulated by NAc MSN subtype-specific activity in a sex-specific manner. Understanding this circuitry has implications for the development of tailored treatment strategies for obesity and other disorders of compulsive consumption.

Stroke survivors frequently develop the flexor synergy, an obligate co-contraction of shoulder abductors and elbow flexors. The neural substrate has to date proven elusive. Here we trained two healthy female monkeys to generate isometric elbow and shoulder torques to move an on-screen cursor, and recorded neuron firing from motor cortical areas and the reticular formation. All regions contained some cells coding for independent contractions about elbow or shoulder. For neurons coding co-contractions, there was a surprising bias: more cells were related to combinations orthogonal to the flexor synergy, e.g. shoulder abduction with elbow extension. We then used threshold microstimulation to examine patterns of muscle activation elicited from the primary motor cortex, reticular formation and spinal cord in five female monkeys. Only in the spinal cord did microstimulation generate coactivation aligned to the flexor synergy. Our results suggest that primitive spinal circuits are limited to synergistic coactivation, a pattern which perhaps evolved for locomotion. Prehensile reaching movements aligned to these synergies require only limited descending control from the cortex and brainstem. By contrast, reaching orthogonal to the flexor synergy relies heavily on descending drive both to suppress spinal circuits and to sculpt motoneuron activity. The findings suggest that apparently similar reaches in different directions have different neural substrates. After a stroke, loss of descending drive leaves movements limited by spinal motor primitives.Significance Statement The flexor synergy is often a major contributor to disability when individuals recover from a stroke. It has been suggested that synergies arise because a surviving neural center has a pre-existing bias to generate co-contraction, and is released from inhibitory control after cortical damage. Here, we show that all brain centers tested were biased to code for co-contractions orthogonal to synergies, making it unlikely that they form the neural substrate. By contrast, spinal microstimulation often generated the same co-activation of muscles as in synergies. Our results suggest that synergies arise from spinal interneurons; this may allow future therapeutic strategies which target spinal circuits.