My Very Occasional Blog

Thanks for reading - Scott

May 23, 2023 - Lessons learned (and learning) after two total knee replacements.
I had my left knee, the one more seriously impacted by osteoarthritis, replaced on Nov. 8, 2022. That went well, so I asked for my other knee to be replaced on May 16, 2023.
It is clear that everyone's experience will differ, even between knees if both of theirs are replaced. Here are some tidbits and suggestions that I hope will help others traverse this event. I will not deal with medications as that is between the patient and his surgeon.
1. Consider purchasing a wedge pillow, 12 inches tall at the thick end. This is convenient for elevation to reduce swelling, especially during the first couple of weeks.
2. Have at least two ice packs to rotate and apply every hour for 30 minutes while awake. Bags of peas wrapped by an ace bandage work. I went with Torex and Onlycare products.
3. Physical therapy to maximize range of motion is essential. Try to flex 90 times per day, either through heels slides aided by a strap or step lunges on the stairs. Push yourself to the point of 8 out of10 on a pain scale on flexion if you can, aiming to get to 130 degrees of flexion within 6 weeks. You do not want to develop adhesions that will need release under anesthesia.
4. Walk as much as reasonable and as suggested by your surgeon and physical therapists.
5. If you were in decent shape beforehand, you should see yourself walking miles by 2 months but I am told that the whole heeling process takes a year.

March 13, 2022 - As I prepare to retire in a few months, here is a brief personal review of some of my lab's research: From Hippocampal CA2 to Social Memory

Key words: vasopressin, Avpr1b, aggression, social recognition, hippocampus

Sometimes it seems that a path to understanding, if not paved, is scattered with coincidences and good luck, including good colleagues. Looking back on our establishment of the connection of the dorsal CA2 area of the hippocampus in mice to social memory and aggression, I see that it may be seen that way.

My postdoctoral work began in the Laboratory of Cell Biology (LCB) at the National Institute of Mental Health which had recruited Ferenc Antoni as a postdoc as well. He had been studying the role of various neuropeptides on the stress response and on pituitary functions. Vasopressin was one of those neuropeptides and in 1984 he found evidence for a novel vasopressin receptor in the pituitary, the vasopressin 1b receptor (Avpr1b) [1]. The LCB was also learning how to clone genes. Stephen Lolait, Anne-Marie O'Carroll, and colleagues cloned the rat vasopressin 1a [2] and vasopressin 2 [3] receptors and eventually the Avpr1b [4]. I had been learning how to make knockout mice, having knocked out (KO) the oxytocin receptor [5]. So, Steve, Anne-Marie, and I and fellow lab mates cloned and knocked out the Avpr1b; and a talented behavioralist, Scott Wersinger, discovered that these mice had deficits in social aggression and social memory [6]. We had all the right pieces at the right time. Subsequently, Scott and Heather Caldwell went on to investigate these mice in more detail behaviorally. Our studies revealed that the Avpr1b KO mice had deficits in maternal aggression but not in predatory or defensive aggression [7, 8] Female mice also had a deficit in social recognition as indicated by the absence of the Bruce effect [9]. Steve and Anne-Marie had moved on to Bristol where they performed a nice series of experiments demonstrating that the KO mice had deficits in acute and chronic stress responses [10-13].

We ruled out an olfactory location for the lack of social memory and aggression in the Avpr1b KO mice [14] but were still befuddled in our attempts to locate expression of the Avpr1b in the rodent brain. Fortunately, an expert neuroanatomist and long-time collaborator in the LCB, Eva Mezey, helped us increase the signal-to-noise ratio in our in situ hybridization histochemical experiments [15] and we were eventually able to find Avpr1b expression in the rat and mouse CA2 area of the hippocampus [16] This prompted us to propose that proper functioning of the CA2 area of the hippocampus was necessary for social memory and social aggression [16] While discussing this finding with then NIMH Scientific Director, Alcinio Silva, he suggested I contact Serena Dudek, a principal investigator at NIH's National Institute of Environmental Health Studies in North Carolina. She had recently shown that the CA2 area had reduced synaptic plasticity [17] This jump-started a series of experiments that focused on the dorsal CA2 area (dCA2). Specifically, Serena and Jerome Pagani were able to demonstrate the necessity for Avpr1b for both proper dCA2 pyramidal neuron excitability in tissue slices and social aggression through viral replacement of Avpr1b there [18] Heather showed that killing of dCA2 neurons with N-methyl D-aspartate (NMDA) reduced social recognition, as in the Avpr1b KO [19] Hitti and Siegelbaum showed a similar finding through inactivation of those neurons [20] Our foray into optogenetics and chemogenetics also proved fruitful. Adam Smith and Sarah Williams Avram virally expressed an excitatory channelrhodopsin in paraventricular vasopressin neurons of male mice and stimulated their nerve terminals in the dCA2 during a 5-minute exposure to a female mouse [21] They found that this stimulation enhanced social memory more than 80-fold in duration and was blocked by an Avpr1b antagonist applied to the CA2 during the stimulation. The stimulation enhanced memory during the initial acquisition exposure but not during the later recall exposure. The stimulation was not effective for enhancing memory for inanimate objects. Finally, the stimulation prevented abrogation of memory by the transient presence of a novel female, an important situation for recalling individuals in situations in which multiple conspecifics are encountered.

Adam and Adi Cymerblit-Sabba also expressed an excitatory designer receptor exclusively activated by designer drugs (DREADD) in the paraventricular vasopressin neurons of mice. The receptor was activated during overnight cohabitation. The males subsequently spent more time in social contact, grooming and huddling with the partner compared to a novel female [22] These results suggested that PVN-to-CA2 projections are part of an evolutionarily conserved neural circuitry underlying the formation of social preference and may promote behavioral changes with appropriate stimulation.

Interest in the dCA2 has grown tremendously over the past decade and a review would exceed this short history in our lab. However, a few questions that we and others are pondering are worth mentioning. A fortuitous collaboration with Howard Eichenbaum's lab suggested that the Avpr1b in dCA2 pyramidal neurons are important for keeping track of temporal order [23] Are these results consistent with a role for the dCA2 neurons as timekeepers [24]? How is it that the constitutive absence of the NMDA obligatory subunit coded by Grin1 in Avpr1b neurons of mice can develop normal aggression as well as short-term social and object memory performance [25] Finally, will we be able to understand the coding or processing of information by dCA2 and how that impacts memory formation by studying its firing patterns of its pyramidal neurons? [26, 27]?

Acknowledgements: I would like to thank the many fellows and other colleagues who have helped me pursue this course of research over the years in Section on Neural Gene Expression, National Institute of Mental Health, National Institutes of Health, Bethesda, MD. I am grateful for the support of intramural research program of the NIMH (ZIAMH002498) and the opportunities it has provided me.

1. Antoni F, Holmes M, Makara G, Karteszi M, Laszlo F. Evidence that the effects of arginine-8-vasopressin (AVP) on pituitary corticotropin (ACTH) release are mediated by a novel type of receptor. Peptides 1984; 5(3): 519-522.
2. Morel A, O'Carroll AM, Brownstein MJ, Lolait SJ. Molecular cloning and expression of a rat V1a arginine vasopressin receptor. Nature 1992; 356(6369): 523-526.
3. Lolait SJ, O'Carroll AM, McBride OW, Konig M, Morel A, Brownstein MJ. Cloning and characterization of a vasopressin V2 receptor and possible link to nephrogenic diabetes insipidus. Nature 1992; 357(6376): 336-339.
4. Lolait SJ, O'Carroll AM, Mahan LC, Felder CC, Button DC, Young WS et al. Extrapituitary expression of the rat V1b vasopressin receptor gene. Proc Natl Acad Sci U S A 1995; 92(15): 6783-6787.
5. Young WS, Shepard E, Amico J, Hennighausen L, Wagner KU, LaMarca ME et al. Deficiency in mouse oxytocin prevents milk ejection, but not fertility or parturition. J Neuroendocrinol 1996; 8(11): 847-853.
6. Wersinger SR, Ginns EI, O'Carroll AM, Lolait SJ, Young WS. Vasopressin V1b receptor knockout reduces aggressive behavior in male mice. Mol Psychiat 2002; 7(9): 975-984.
7. Wersinger SR, Caldwell HK, Christiansen M, Young WS. Disruption of the vasopressin 1b receptor gene impairs the attack component of aggressive behavior in mice. Genes Brain Behav 2007; 6(7): 653-660.
8. Caldwell HK, Wersinger SR, Young WS. The role of the vasopressin 1b receptor in aggression and other social behaviours. Prog Brain Res 2008; 170: 65-72.
9. Wersinger SR, Temple JL, Caldwell HK, Young WS. Inactivation of the oxytocin and the vasopressin (Avp) 1b receptor genes, but not the Avp 1a receptor gene, differentially impairs the Bruce effect in laboratory mice (Mus musculus). Endocrinology 2008; 149(1): 116-121.
10. Lolait SJ, Stewart LQ, Roper JA, Harrison G, Jessop DS, Young WS et al. Attenuated stress response to acute lipopolysaccharide challenge and ethanol administration in vasopressin V1b receptor knockout mice. J Neuroendocrinol 2007; 19(7): 543-551.
11. Lolait SJ, Stewart LQ, Jessop DS, Young WS, O'Carroll AM. The hypothalamic-pituitary-adrenal axis response to stress in mice lacking functional vasopressin V1b receptors. Endocrinology 2007; 148(2): 849-856.
12. Stewart LQ, Roper JA, Young WS, O'Carroll AM, Lolait SJ. Pituitary-adrenal response to acute and repeated mild restraint, forced swim and change in environment stress in arginine vasopressin receptor 1b knockout mice. J Neuroendocrinol 2008; 20(5): 597-605.
13. Roper JA, Craighead M, O'Carroll AM, Lolait SJ. Attenuated stress response to acute restraint and forced swimming stress in arginine vasopressin 1b receptor subtype (Avpr1b) receptor knockout mice and wild-type mice treated with a novel Avpr1b receptor antagonist. J Neuroendocrinol 2010; 22(11): 1173-1180.
14. Wersinger SR, Kelliher KR, Zufall F, Lolait SJ, O'Carroll AM, Young WS. Social motivation is reduced in vasopressin 1b receptor null mice despite normal performance in an olfactory discrimination task. Horm Behav 2004; 46(5): 638-645.
15. Young WS, Mezey É. Hybridization Histochemistry. In: Crawley J, Gerfen C, Rogawski M, Sibley D, Skolnik P, Wray S (eds). Current Protocols in Neuroscience. John Wiley & Sons: New York, 2006, pp 1.3.1-1.3-20.
16. Young WS, Li J, Wersinger SR, Palkovits M. The vasopressin 1b receptor is prominent in the hippocampal area CA2 where it is unaffected by restraint stress or adrenalectomy. Neuroscience 2006; 143(4): 1031-1039.
17. Zhao M, Choi YS, Obrietan K, Dudek SM. Synaptic plasticity (and the lack thereof) in hippocampal CA2 neurons. J Neurosci 2007; 27(44): 12025-12032.
18. Pagani JH, Zhao M, Cui Z, Avram SK, Caruana DA, Dudek SM et al. Role of the vasopressin 1b receptor in rodent aggressive behavior and synaptic plasticity in hippocampal area CA2. Mol Psychiat 2015; 20(4): 490-499.
19. Stevenson E, Young WS, Caldwell HK. The effects of excitotoxic lesions of the CA2 region of the hippocampus on social recognition in male mice. Soci Neurosci Abstracts 2011.
20. Hitti FL, Siegelbaum SA. The hippocampal CA2 region is essential for social memory. Nature 2014; 508(7494): 88-92.
21. Smith AS, Williams Avram SK, Cymerblit-Sabba A, Song J, Young WS. Targeted activation of the hippocampal CA2 area strongly enhances social memory. Mol Psychiat 2016.
22. Cymerblit-Sabba A, Smith AS, Williams Avram SK, Stackmann M, Korgan AC, Tickerhoof MC et al. Inducing Partner Preference in Mice by Chemogenetic Stimulation of CA2 Hippocampal Subfield. Front Mol Neurosci 2020; 13: 61.
23. DeVito LM, Konigsberg R, Lykken C, Sauvage M, Young WS, Eichenbaum H. Vasopressin 1b receptor knock-out impairs memory for temporal order. J Neurosci 2009; 29(9): 2676-2683.
24. MacDonald CJ, Tonegawa S. Crucial role for CA2 inputs in the sequential organization of CA1 time cells supporting memory. Proc Natl Acad Sci U S A 2021; 118(3).
25. Williams Avram SK, Lee HJ, Fastman J, Cymerblit-Sabba A, Smith A, Vincent M et al. NMDA Receptor in Vasopressin 1b Neurons Is Not Required for Short-Term Social Memory, Object Memory or Aggression. Front Behav Neurosci 2019; 13: 218.
26. Donegan ML, Stefanini F, Meira T, Gordon JA, Fusi S, Siegelbaum SA. Coding of social novelty in the hippocampal CA2 region and its disruption and rescue in a 22q11.2 microdeletion mouse model. Nat Neurosci 2020; 23(11): 1365-1375.
27. Cymerblit-Sabba A, Stackmann M, Williams Avram S, Granovetter MC, Cliz NI, Pereira F et al. Recognition memory via repetition suppression in mouse hippocampal dorsal CA2 pyramidal neurons expressing the vasopressin 1b receptor. bioRxiv 2020; doi: 10.1101/2020.05.11.078915.

March 13, 2022 - Follow-up on the Honda Clarity - it has been discontinued.
I must say that I'm somewhat surprised but, on the other hand, maybe this means that they are hastening a change to all-electric with the Honda Prologue due in 2024 in collaboration with GM and Sony, I believe. I have been very happy with the Clarity, my only concern being that the battery life has declined about 15% since purchased...

June 26, 2018 - I could begin by complaining/ranting about the condition of the United States of America, but that's for another day...

Instead, want to hear about my new (well, since May 13th) 2018 Honda Clarity?
Thought so. It is spacious. Nice for a plug-in hybrid electric vehicle (PHEV - fev?). Charges fine overnght at 120V - just don't use the Honda Link scheduling app. If you plug in after the set time, it doesn't charge that night! It is a relatively smooth ride and quiet as well, especially on electric. I can drive to and from work each day and not use up the 47 miles of battery. Sweet. My friends say that I should be concerned about gas stagnating in the tank but I think I will take longer trips to replace the gas often enough. We'll see. Pay attention to the Economy mode. I have caught it turning off occasionally - I don't think it's anything that I have done but it bears further watching.

Not a big fan of the display but it works well enough. Doesn't always sense my attached iPhone so I need to unplug it and re-plug it in. I've read that Apple CarPlay's next update will enable use of Waze. That's good as Apple Maps still sends you in odd directions and dead ends.

Finally, for this entry, my main complaint is that there is no way to prevent entry into the trunk after breaking into the front. There is no interior lock as there was in my Accord. Sure, if you break in and push the trunk release, the alarm will go off, but if they are fast, you will be out of luck. And there is no valet key. Someone was not on the ball.

Comments? Drop me a friendly line, please.