The Neuropeptide Tac2 Controls a Distributed Brain State Induced by Chronic Social Isolation Stress

Zelikowsky, Moriel; Hui, May; Karigo, Tomomi; Choe, Andrea; Yang, Baohua; Blanco, Mario R.; Beadle, Keith; Gradinaru, Viviana; Deverman, Benjamin E.; Anderson, David J.

doi:10.1016/j.cell.2018.03.037

Cited by 234 publications

(282 citation statements)

References 96 publications

Supporting

Mentioning

261

Contrasting

Unclassified

Order By: Relevance

“…Behavioral changes observed following 2 weeks of isolation appeared to be mediated by TAC2 upregulation in discrete sites, as chemogenetic silencing of TAC2‐expressing neurons in the adBNST, CeA, or DMH selectively prevented persistent freezing, acute freezing, or aggression, respectively . Notably, ∼50% of TAC2‐expressing neurons in the adBNST and CeA co‐expressed CRF, which again highlights the involvement of CRF circuits in isolation‐induced adaptation. A substantial body of work supports a role for the BNST in mediating sustained responses, and the CeA in mediating rapid responses, to potential/unpredictable threats .…”

Section: Homeostatic Response To Social Deficit: Engaging Social Motimentioning

confidence: 80%

“…Interestingly, it was recently revealed that an intermediate duration of isolation in mice (2 weeks) is associated with upregulation of the neuropeptide tachykinin 2 (TAC2; also known as neurokinin B) in several regions including the anterodorsal BNST (adBNST), CeA, and dorsomedial hypothalamus (DMH), with levels gradually increasing from just 30 min post‐isolation . Behavioral changes observed following 2 weeks of isolation appeared to be mediated by TAC2 upregulation in discrete sites, as chemogenetic silencing of TAC2‐expressing neurons in the adBNST, CeA, or DMH selectively prevented persistent freezing, acute freezing, or aggression, respectively . Notably, ∼50% of TAC2‐expressing neurons in the adBNST and CeA co‐expressed CRF, which again highlights the involvement of CRF circuits in isolation‐induced adaptation.…”

Section: Homeostatic Response To Social Deficit: Engaging Social Motimentioning

confidence: 99%

See 1 more Smart Citation

Neural mechanisms of social homeostasis

Matthews

Tye

2019

Annals of the New York Academy of Sciences

126

101

View full text Add to dashboard Cite

Social connections are vital to survival throughout the animal kingdom and are dynamic across the life span. There are debilitating consequences of social isolation and loneliness, and social support is increasingly a primary consideration in health care, disease prevention, and recovery. Considering social connection as an “innate need,” it is hypothesized that evolutionarily conserved neural systems underlie the maintenance of social connections: alerting the individual to their absence and coordinating effector mechanisms to restore social contact. This is reminiscent of a homeostatic system designed to maintain social connection. Here, we explore the identity of neural systems regulating “social homeostasis.” We review findings from rodent studies evaluating the rapid response to social deficit (in the form of acute social isolation) and propose that parallel, overlapping circuits are engaged to adapt to the vulnerabilities of isolation and restore social connection. By considering the neural systems regulating other homeostatic needs, such as energy and fluid balance, we discuss the potential attributes of social homeostatic circuitry. We reason that uncovering the identity of these circuits/mechanisms will facilitate our understanding of how loneliness perpetuates long‐term disease states, which we speculate may result from sustained recruitment of social homeostatic circuits.

show abstract

Section: Homeostatic Response To Social Deficit: Engaging Social Motimentioning

confidence: 80%

Section: Homeostatic Response To Social Deficit: Engaging Social Motimentioning

confidence: 99%

Neural mechanisms of social homeostasis

Matthews

Tye

2019

Annals of the New York Academy of Sciences

126

101

View full text Add to dashboard Cite

show abstract

“…Enhancing NKB expression and release phenocopied social isolation stress in group-housed mice, promoting aggression and converting stimulus-locked defensive behaviors to persistent responses. The multiple behavioral changes evoked by brain-wide upregulation of TAC2/neurokinin B could be blocked by systemic administration of an NK3R antagonist (Zelikowsky et al 2018). …”

Section: Memory Of Painmentioning

confidence: 99%

Substance P and pain chronicity

2018

View full text Add to dashboard Cite

Substance P (SP) is a highly conserved member of the tachykinin peptide family that is widely expressed throughout the animal kingdom. The numerous members of the tachykinin peptide family are involved in a multitude of neuronal signaling pathways, mediating sensations and emotional responses (Steinhoff et al. in Physiol Rev 94:265–301, 2014). In contrast to receptors for classical transmitters, such as glutamate (Parsons et al. in Handb Exp Pharmacol 249–303, 2005), only a minority of neurons in certain brain areas express neurokinin receptors (NKRs) (Mantyh in J Clin Psychiatry 63:6–10, 2002). SP is also expressed by a variety of non-neuronal cell types such as microglia, as well as immune cells (Mashaghi et al. in Cell Mol Life Sci 73:4249–4264, 2016). SP is an 11-amino acid neuropeptide that preferentially activates the neurokinin-1 receptor (NK1R). It transmits nociceptive signals via primary afferent fibers to spinal and brainstem second-order neurons (Cao et al. in Nature 392:390–394, 1998). Compounds that inhibit SP’s action are being investigated as potential drugs to relieve pain. More recently, SP and NKR have gained attention for their role in complex psychiatric processes. It is a key goal in the field of pain research to understand mechanisms involved in the transition between acute pain and chronic pain. The influence of emotional and cognitive inputs and feedbacks from different brain areas makes pain not only a perception but an experience (Zieglgänsberger et al. in CNS Spectr 10:298–308, 2005; Trenkwaldner et al. Sleep Med 31:78–85, 2017). This review focuses on functional neuronal plasticity in spinal dorsal horn neurons as a major relay for nociceptive information.

show abstract

“…was determined based on the live visualization of (anesthetized) neural activity as the lens was inserted. 38 Metabond was used to stabilize the lens, and Kwik-Sil sealant (World Precision Instruments) was used to 39 cover the lens surface. After another 2-3 weeks, mice were anesthetized for placement of a 40 microendoscope baseplate (cat# 1050-002192, Inscopix) and a baseplate cover (catalogue #1050-002193, 41…”

Section: Extended Datamentioning

confidence: 99%

Stimulus-specific neural encoding of a persistent, internal defensive state in the hypothalamus

Kennedy

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

14Persistent neural activity has been described in cortical, hippocampal, and motor networks as 15 mediating short-term working memory of transiently encountered stimuli 1-4 . Internal emotion states 16 such as fear also exhibit persistence following exposure to an inciting stimulus 5,6 , but such 17 persistence is typically attributed to circulating stress hormones 7-9 ; whether persistent neural activity 18 also plays a role has not been established. SF1 + /Nr5a1 + neurons in the dorsomedial and central 19 subdivision of the ventromedial hypothalamus (VMHdm/c) are necessary for innate and learned 20 defensive responses to predators 10-13 . Optogenetic activation of VMHdm SF1 neurons elicits defensive 21 behaviors that can outlast stimulation 11,14 , suggesting it induces a persistent internal state of fear or 22 anxiety. Here we show that VMHdm SF1 neurons exhibit persistent activity lasting tens of seconds, in 23 response to naturalistic threatening stimuli. This persistent activity was correlated with, and 24 required for, persistent thigmotaxic (anxiety-like) behavior in an open-field assay. Microendoscopic 25 imaging of VMHdm SF1 neurons revealed that persistence reflects dynamic temporal changes in 26 population activity, rather than simply synchronous, slow decay of simultaneously activated 27 neurons. Unexpectedly, distinct but overlapping VMHdm SF1 subpopulations were persistently 28 activated by different classes of threatening stimuli. Computational modeling suggested that 29 recurrent neural networks (RNNs) incorporating slow excitation and a modest degree of 30 neurochemical or spatial bias can account for persistent activity that maintains stimulus identity, 31 without invoking genetically determined "labeled lines" 15 . Our results provide causal evidence that 32 persistent neural activity, in addition to well-established neuroendocrine mechanisms, can 33 contribute to the ability of emotion states to outlast their inciting stimuli, and suggest a mechanism 34 3 that could prevent over-generalization of defensive responses without the need to evolve hardwired 35 circuits specific for each type of threat. (267 words) 36 Main Text 37We performed fiber photometry 16 in VMHdm SF1 neurons expressing GCaMP6s 17 in freely behaving mice 38 during a 10s presentation of a predator (an anesthetized rat 18 ) ( Fig. 1a-c). We observed a rapid 39 increase in the bulk calcium signal at the onset of rat presentation ( Fig. 1d, e). Remarkably, this activity 40 persisted for over a minute following rat removal, decaying exponentially with time constant τdecay = 41 26.7±2.2 seconds ( Fig. 1d-e, h-i; Supplemental Video 1). In contrast, a toy rat presented in the same 42 manner produced a far weaker and less persistent response ( Fig. 1d, e). 43 To better control the timing and location of stimulus presentation, we repeated this experiment 44 using a head-fixed preparation. The magnitude, decay constants and specificity of VMHdm SF1 persistent 45 responses were comparable to those measured in freely behaving mice ( Fig...

show abstract

The Neuropeptide Tac2 Controls a Distributed Brain State Induced by Chronic Social Isolation Stress

Cited by 234 publications

References 96 publications

Neural mechanisms of social homeostasis

Neural mechanisms of social homeostasis

Substance P and pain chronicity

Stimulus-specific neural encoding of a persistent, internal defensive state in the hypothalamus

Contact Info

Product

Resources

About